Skip to main content
Download PDF

The function of LncRNA-H19 in cardiac hypertrophy

Cell & Bioscience volume 11, Article number: 153 (2021) Cite this article

Abstract

Cardiac hypertrophy, characterized by the enlargement of cardiomyocytes, is initially an adaptive response to physiological and pathological stimuli. Decompensated cardiac hypertrophy is related to fibrosis, inflammatory cytokine, maladaptive remodeling, and heart failure. Although pathological myocardial hypertrophy is the main cause of hypertrophy-related morbidity and mortality, our understanding of its mechanism is still poor. Long noncoding RNAs (lncRNAs) are noncoding RNAs that regulate various physiological and pathological processes through multiple molecular mechanisms. Recently, accumulating evidence has indicated that lncRNA-H19 is a potent regulator of the progression of cardiac hypertrophy. For the first time, this review summarizes the current studies about the role of lncRNA-H19 in cardiac hypertrophy, including its pathophysiological processes and underlying pathological mechanism, including calcium regulation, fibrosis, apoptosis, angiogenesis, inflammation, and methylation. The context within which lncRNA-H19 might be developed as a target for cardiac hypertrophy treatment is then discussed to gain better insight into the possible biological functions of lncRNA-H19 in cardiac hypertrophy.

Introduction

Hypertrophic cardiomyopathy (HCM) is a common inherited disease characterized by an increase in the thickness of the ventricular wall (≥ 1.5 cm) in the absence of increased afterload, and it is recognized as an important cause of sudden cardiac death among young adults and competitive athletes [1]. In recent years, abundant data have revealed that HCM occurs at a rate of approximately 1/500 in the general population [2], but other data indicate a prevalence of HCM and genetic carriers of 1/200 [3]. Cardiac hypertrophy (CH), characterized by an increase in cardiomyocyte size, rather than an increase in their number, is initially a compensatory response to cope with biomechanical stresses and facilitate the maintenance of proper cardiac output and homeostasis [4, 5].

CH has been categorized as either pathological or physiological hypertrophy. Physiological CH is generally caused by normal growth, pregnancy, or exercise. Pathological CH is the heart’s maladaptive reaction to various pathological stimuli, such as high blood pressure, myocardial infarction, and many more [6]. Pathological CH is related to myocardial fibrosis, calcium (Ca2+) dysregulation, increased inflammatory cytokine, and epigenetic changes, which lead to maladaptive cardiac remodeling, heart failure (HF), and death [7, 8]. The progression of both physiological and pathological hypertrophy depends on upstream stimuli and signaling mechanisms rather than cardiac stress [9,10,11]. The current efficiency of CH treatment is improving rapidly, but the mortality rate of HF remains at approximately 50% 5 years after diagnosis [12]. Therefore, identifying the fundamental molecular mechanisms underlying CH is a vital challenge for HF treatment.

In the past decade, numerous studies have found that some regulatory mechanisms, including cellular metabolism [13], proliferation [6], miRNAs [14,15,16], immune responses [17, 18], translational regulation [19], and epigenetic modifications [20, 21], positively or negatively regulate CH. Global transcriptome analyses have identified a few lncRNAs that are critically involved in CH [22,23,24].

Recently, long noncoding RNAs (lncRNAs), which are more than 200 nucleotides in length and lack protein-coding capacity [25], have been shown to be involved in many cellular processes and the development of various diseases [26, 27]. By interacting with RNA, DNA and proteins, lncRNAs can regulate the expression of genes involved in many biological activities [28, 29], such as RNA processing [30], apoptosis [31], genome rearrangement and chromatin modification [32, 33], and competing endogenous RNAs (ceRNAs) [34, 35], at multiple levels. Therefore, lncRNAs are dynamically expressed in a range of differentiation processes, including those of embryonic stem cells [36, 37], vascular smooth muscle cells [38], muscles [39], T cells [40], breast tissues [41] and neurons [42], as well as in cancer [42, 43] and other diseases [44, 45]. Moreover, many studies have shown that lncRNAs are important regulators in many pathophysiological processes of heart development and diseases [22, 46, 47], such as cardiac organogenesis [48], atherosclerosis [49,50,51], hypertension [38, 52, 53], pulmonary arterial hypertension [54], coronary artery disease [55, 56], ischemia/reperfusion-induced apoptosis [57], HF [58], and CH (Table 1). All these results suggest that lncRNAs play a central role in the occurrence of human diseases, including cardiovascular diseases.

Table 1 Anti- and pro-hypertrophic lncRNAs and their regulated genes
Full size table

H19, which is a maternally expressed and paternally imprinted 2.7-kb gene, is localized near the telomeric region of chromosome 11p15.5 and is reciprocally imprinted and regulated with its neighboring gene, insulin-like growth factor 2 (IGF2) [28, 87, 88]. H19 is highly evolutionarily conserved, suggesting that it may have some crucial biological functions [89]. Intriguingly, H19 is most highly expressed in skeletal muscle and exhibits an ~ tenfold enrichment in cardiac tissue over all other mouse tissues (such as brain, lung, kidney, and many more) [68].

Emerging evidence shows that diverse cells, such as hematopoietic stem cells [90] and neurons [91, 92], and cellular processes, including abdominal aortic aneurysm [93], diabetic nephropathy [94], hepatocyte proliferation [95, 96], tumorigenesis [97, 98], acute promyelocytic leukemia [99], ulcerative colitis [100], senescence [101], and endometriosis [102], are regulated by H19. Moreover, accumulating evidence indicates that H19 is a powerful regulator of cardiac development and pathophysiology, such as endothelial aging [103], mineralization of aortic valves [104], ischemia/reperfusion injury [105, 106], and atherosclerosis [107]. All these studies show that H19 plays a crucial role in the occurrence and development of heart disease and will become a new hot spot and focus of cardiovascular basic and clinical research.

H19 expression is dynamically regulated, and it is involved in multiple pathways of different cardiac cell types to exert distinct cell type-specific effects. In different stages of CH, H19 expression is different. During the process of heart maturation after birth and with age, the expression of H19 gradually decreases [67] but increases within 2 weeks after transverse aortic constriction (TAC, a surgical procedure that induces CH) in a mouse model [67, 108]. Nonetheless, H19 expression was significantly decreased during the progression from the compensated stage to the decompensated stage of HF (4–6 weeks after TAC) and remained low until the experimental endpoint 13 weeks after TAC [68]. Of note, due to differences in mean age between patients with diseased and healthy hearts, lower levels of H19 expression in human heart tissues may be partially attributed to an age-related reduction.

During the pathogenesis of CH, intracellular signals, such as calcium regulation, are regulated to promote the translocation of the hypertrophy-related transcription factor NFAT to regulate the expression of downstream hypertrophy genes. These signals promote myocardial fibrosis and CH. The long-term presence of stress promotes angiogenesis, inflammation, and then apoptosis, ultimately leading to heart failure. Numerous investigations have shown that H19 is involved in some of these pathophysiologies. Herein, we summarized the current studies on H19 in CH-related pathophysiological processes (Fig. 1) to explain the potential therapeutic value of H19 in HCM and provide a basis for further investigation.

Fig. 1
figure 1

The role of H19 and its targets in CH-related pathophysiological processes and the potential mechanisms. AMPK adenosine 5′-monophosphate (AMP)-activated protein kinase, CaMKIIδ Ca2+/calmodulin-dependent protein kinase IIδ, CN calcineurin, CTGF connective tissue growth factor, DUSP5 dual-specificity phosphatase 5, E2F1 E2F transcription factor 1, EZH2 enhancer of zeste homolog 2, FADD fas-associated protein with death domain, HIF-1α hypoxia-inducible factor 1α, ICAM-1 intercellular adhesion molecule 1, JNK jun n-terminal kinases, KDM3A Lysine (K)-specific demethylase 3 A, MDM2 mouse 3T3 cell double minute 2, NFAT nuclear factor of activated T cell, PA2G4 proliferation-associated protein 2G4, PRC2 polycomb suppression complex 2, RIPK receptor-interacting serine/threonine-protein kinase 1 and 3, STAT3 signal transducer and activator of transcription 3, VCAM-1 vascular cell adhesion molecule 1, VDAC1 voltage-dependent anion channel 1, YB-1 Y-box-binding protein-1

Full size image

LncRNA-H19 controls the function of calcium channels

Cyclic changes in calcium (Ca2+) in cardiomyocytes regulate the contraction of the heart [109, 110]. Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ) is associated with the phosphorylation of some Ca2+-regulating proteins and has been shown to act as an inducer of CH [111,112,113]. Moreover, evidence emphasizes that Ca2+ dysregulation plays a key role in the development of CH [114].

H19, as the precursor of miR-675, which inhibits the expression of CaMKIIδ, is a negative regulator of CH. Exon 1 of H19 contains a miRNA-containing hairpin, and it has been shown that miR-675 can confer functionality to H19 [115, 116]. The mRNA 3′-UTR of miR-675, a miRNA embedded in H19’s first exon, matches the sequence of CaMKIIδ. Liu et al. revealed that the H19-miR-675-CaMKIIδ axis plays a crucial role in CH. The expression of H19 and miR-675 were found to be upregulated in pathological cardiac hypertrophy, and CaMKIIδ was shown to be a direct target of miR-675 and to partially mediate the effect of H19 on cardiomyocytes, indicating that miR-675-regulated CaMKIIδ might mediate the H19-induced inhibition of cardiomyocyte hypertrophy. Similarly, another study found that CaMKIIδ expression was upregulated after the suppression of H19 expression in a rat right ventricular failure model established by pulmonary artery banding [58]. Nonetheless, Thum, who found that repression or overexpression of H19 had no influence on the expression levels of CaMKIIδ, thought that these antihypertrophic effects are H19-specific and independent of miR-675 [68]. It may be that the expression levels of CaMKIIδ are different at different stages and that many other molecules can activate CaMKIIδ. The levels of CaMKIIδ increase as early as 2 days and continuously for up to 7 days after TAC surgery [117]. In addition, splice variants of the CaMKIIδ isoform, characterized by the presence of a second variable domain, include CaMKII δB and CaMKIIδC [118]. Consequently, further research is required to investigate which isoform of CaMKIIδ mediates the H19-induced inhibition of cardiomyocyte hypertrophy.

LncRNA-H19 regulates transcription factors

Methylation has been implicated as one of the modulators of cardiac gene expression in development and disease [119]. A study revealed that trimethylation of histone H3 at lysine (K) 4, K9, or K27 and dimethylation of H3 at K9 and K79 were associated with hypertrophic heart phenotypes [120]. Different lncRNAs were shown to favor or prevent binding and methylation by interacting with polycomb suppression complex 2 (PRC2) [21, 46], which trimethylates lysine residue 27 on histone H3 [121]. Viereck et al. found that H19 exerts its antihypertrophic function by targeting the prohypertrophic nuclear factor of activated T cell (NFAT) signaling pathway [68]. H19 interacts with PRC2 to suppress H3K27 trimethylation (H3K27me3) of the antihypertrophic Tescalcin locus, resulting in a decrease in the expression and activity of NFAT. Furthermore, in vitro and in vivo, the absence of H19 leads to repression of Tescalcin, which in turn increases NFAT levels and effects on its pro-hypertrophic target genes. These studies suggest that H19-mediated regulation of methylation might alleviate the progression of pathological hypertrophy.

LncRNA-H19 regulates cardiac fibrosis

Fibrosis is characterized by the net accumulation of extracellular matrix (ECM) proteins and develops because of fibroblast differentiation during the process of inflammation [122]. In a normal heart, cardiac fibroblasts generate ECM components, such as collagen type I and type III. Cardiac fibrosis, which occurs due to the aberrant deposition of ECM proteins in the cardiac interstitium, leads to systolic and/or diastolic dysfunction in many cardiac pathological conditions, including myocardial infarction, cardiomyopathy, and HF, resulting in serious cardiac dysfunction [123].

Studies show that H19 is highly associated with organ fibrosis, including liver fibrosis [96], lung fibrosis [124], renal fibrosis [56], and cardiac fibrosis [125, 126]. Evidence has demonstrated that H19-mediated regulation of DUSP5 affects ERK1/2 phosphorylation, increasing cardiac fibroblast proliferation and fibrosis [127]. Another study revealed that H19 knockdown could enhance the antifibrotic role of miR-455, decrease connective tissue growth factor (CTGF) expression, and further reduce fibrosis-associated protein synthesis [128]. Moreover, in phenylephrine-induced pathological cardiomyocyte hypertrophy, H19 knockdown upregulated the expression of enhancer of zeste homolog 2 (EZH2) [126], which is known to target cardiac myocytes and silence hypertrophic and fibrotic gene programs [129]. Additionally, Choong et al. verified that H19 acted to antagonize Y-box-binding protein-1 (YB-1) through direct interaction under hypoxic conditions, which led to the downregulation of Collagen 1A1 expression and cardiac fibrosis, aggravating cardiac remodeling [125]. The above experimental results suggest that H19 directly or indirectly promotes cardiac fibrosis by acting as a molecular sponge or interacting with various proteins to regulate gene expression.

However, other studies obtained the opposite results. The expression of H19 in cardiomyocytes, among the major cardiac cell types, is lower than that in endothelial cells but higher than that in cardiac fibroblasts, and H19 regulates cardiac fibroblast proliferation and fibrosis [68].

These experiments suggest that H19 may be involved in the different pathological processes of CH through different molecular mechanisms, which has established a solid foundation for the future development of novel treatments for cardiac fibrosis.

LncRNA-H19 regulates angiogenesis

Angiogenesis, which is induced by paracrine signals between myocardial cells and the vascular system, is a key component of cardiac remodeling [130]. The development of hypertrophy is affected by capillary density. Vascular endothelial growth factor (VEGF) is an essential angiogenic molecule involved in maintaining myocardial capillary density. In pathological hypertrophy, capillary density and coronary blood flow reserve are not enough to support myocardial growth, leading to mild hypoxia and nutritional insufficiency of the myocardium [131].

Research has revealed that H19 is involved in vascular angiogenesis. H19 knockdown led to a dramatic reduction in endothelial cell (EC) growth and formation of a capillary-like structure, which was related to cell cycle inhibition [132]. Additionally, another study showed that the endothelium-specific inhibition of H19 could impair angiogenesis, while exogenous H19 could partially protect this effect [103]. Moreover, Zhu et al. reported that H19 overexpression also increases VEGF protein levels and endothelial NO synthase (eNOS) levels in human dermal vascular endothelial cells (HMEC-1) by downregulating miR-181a expression and activating the JNK and AMPK signaling pathways, suggesting that H19 exerts proangiogenic effects by regulating VEGF and eNOS [133]. The above experimental results show that H19 promotes angiogenesis under both physiological and pathological conditions.

Hypoxia-inducible factor 1α (HIF-1α) is a transcription factor that acts as a master regulator of oxygen homeostasis by regulating angiogenesis and glucose metabolism and plays a key protective role in the pathophysiology of pathological hypertrophy [134]. The ubiquitylation of HIF1α leads to a mismatch between myocardial growth and capillary density, thereby facilitating the development of maladaptive CH [135]. Intriguingly, in the nucleus of smooth muscle cells, accumulated H19 binds to the promoter region of HIF1α and recruits the transcription factor Sp1, which enhances HIF1α expression [93]. Whether H19 regulates HIF1α in cardiomyocytes is currently unclear.

These studies suggest that H19 regulates angiogenesis, which is a critical cause of CH. However, the specific mechanism underlying in myocardial hypertrophy needs further study.

LncRNA-H19 regulates the inflammatory response

Studies have shown that H19 is involved in several kinds of inflammatory responses [136, 137], which are also involved in the pathogenesis of CH [138,139,140].

Some transcription factors of the inflammatory response, such as nuclear factor-κB (NF-κB), have been recognized to be related to the process of CH [141, 142]. Celecoxib, a classic anti-inflammatory agent, markedly prevents the expression of multiple inflammatory factors, including ICAM‐1, PAI‐1, and TNF‐α, in hypertrophic hearts via inhibition of the AKT/‐mTOR/NF‐κB signaling pathway [142]. When responding to inflammatory signals, NF-κB plays a pathogenic role in inflammation. NF-κB enhances interleukin 6 (IL-6) expression by downregulating microRNA let-7. A recent study in mice with TAC provided new insight into hypoxia-induced mitogenic factor (HIMF), a cytokine-like protein that can induce CH by regulating IL-6 [143].

In human umbilical vein endothelial cells (HUVECs), H19 depletion favors a pro-inflammatory environment characterized by IL-6 signaling and STAT3 activation [103]. Additionally, H19 can regulate inflammatory responses by directly targeting let-7. In the latest research, in a mouse model of abdominal aortic aneurysm (AAA), H19 overexpression in VSMCs increased IL-6 expression, promoted vascular inflammation, and ultimately induced AAA development [144]. This report suggests a possible H19/NF-κB/let-7/IL-6 pathway by which H19 regulates CH-related inflammatory responses.

LncRNA-H19 regulates cellular apoptosis

In the normal heart, apoptosis occurs at rare low rates. However, in heart disease, this rate increases, which results in decompensated hypertrophy and HF, based on animal studies [145, 146]. Overexpression of H19 in vascular smooth muscle cells (VSMCs) and human umbilical vein endothelial cells (HUVECs) induces an increase in proliferation and a decrease in apoptosis [147]. Moreover, it has been reported that H19 promotes proliferation and inhibits apoptosis by modulating the WNT/β-catenin signaling pathway via miR-148b in ox-LDL-stimulated human aorta vascular smooth muscle cells (HA-VSMCs), suggesting that H19 may play a role in regulating cellular proliferation and apoptosis [148]. However, in a rat model of adriamycin-induced dilated cardiomyopathy, H19 was described to promote apoptosis [149]. Another study demonstrated that the H19/miR-675 axis is involved in regulating apoptosis by targeting voltage-dependent anion channel 1 (VDAC1) in cardiomyocytes exposed to high glucose [136]. As far as current research is concerned, H19 can positively or negatively regulate apoptosis, which may provide valuable insights for understanding the pathogenic role of H19 in the development of heart disease.

Through cell shrinkage, chromatin compaction, plasma membrane blebbing, and nuclear fragmentation, apoptosis plays critical roles in the pathogenesis of HCM [150]. The TAC mouse model results in hypertrophy with increased fibrosis, inflammation, cardiomyocyte apoptosis, and persistent CaMKIIδ activation [151]. However, the clear mechanism by which H19 regulates apoptosis in CH needs further study.

LncRNA-H19 regulates cardiac remodeling post myocardial infarction

Myocardial infarction (MI) remains the leading cause of morbidity and mortality worldwide, despite significant progress in the treatment and prevention of the disease [152]. In addition to acute myocardial ischemic damage and reperfusion injury, heart failure triggered by the ensuing maladaptive ventricular remodeling can be a truly difficult issue to address [153].

Dynamic regulation of H19 post-MI is involved in multiple pathways of different cardiac cell types, including cardiomyocyte apoptosis and cardiac inflammation. Recently, aberrant expression of H19 has been detected in acute myocardial infarction (AMI) patients [154]. Intriguingly, Choong et al. observed that H19 is slowly upregulated and reaches an exceptionally high level and a significant increase in heart weight at day 4 post-MI [125]. Furthermore, the size of cardiomyocytes increased in H19-overexpressing mice at day 4 post-MI, suggesting that the overexpression of H19 indeed has an effect on cardiac hypertrophy. Further study found H19 competes with COL1A1 promoter to form the H19-YB-1 complex. The function of YB-1 as a suppressor of COL1A1 is abolished, and the expression of Col1a1 is increased and promotes the development of cardiac hypertrophy. In contrast, the study results were inconsistent with other studies, which concluded that H19 has antihypertrophic functions. Viereck et al. unraveled that H19 exerts its antihypertrophic functions by targeting the pro-hypertrophic nuclear factor of activated T cells (NFAT) signaling [68]. More recently, H19 could inhibit CYP1B1 expression in a PBX3-dependent manner to suppress cell apoptosis and promote cell proliferation, thus attenuating myocardial infarction [155]. Zhang and colleagues found that forced H19 expression could dramatically reduce myocardial infarction size, improve cardiac performance and alleviate cardiac fibrosis by mitigating myocardial apoptosis and decreasing inflammation [156]. Subsequent molecular mechanism experiments verified that H19 could function as an endogenous sponge to competitively bind to miR-22-3p to ameliorate MI-induced myocardial damage by upregulating the expression of KDM3A, which participated in left ventricular hypertrophy in response to pressure overload [157]. A potential explanation for this discrepancy is that lncRNAs can be differentially expressed in different cell types to exert distinct cell type-specific functions [22, 158].

As a result, H19 regulates cardiac remodeling through different mechanisms, such as transcriptional regulation, and serves as a microRNA sponge to inhibit microRNA function to attenuate myocardial infarction and MI-induced myocardial damage. However, further research is required to investigate whether there are other mechanisms that link H19 and the pathological process of AMI.

By genetic analysis, a recent study suggested a significant association between H19 gene variants and HCM [159], which requires validation in other large cohorts and functional studies to define the biological effect of these nucleotide changes. In addition, CH is also accompanied by changes in metabolism [160], oxidative stress [161], mitochondrial homeostasis [162], etc. However, whether H19 regulates these processes is still largely unknown, and the mechanism needs to be further elucidated.

Conclusions

The goal of HCM therapy is to alleviate symptoms and prevent sudden death by the prohibition of competitive sports participation, septal alcohol ablation, septal myectomy, the implantation of cardioverter-defibrillators (ICDs) if needed, and cardiac transplantation [12]. With the elucidation of the underlying mechanism of pathological hypertrophy, many new perspectives for the targeted therapy of CH have been proposed. Mavacamten, named MYK-461, as an orally administered, small-molecule modulator of cardiac myosin, could selectively attenuate the activity of myosin ATPase to improve exercise capacity, left ventricular outflow tract obstruction, and health status in patients with obstructive hypertrophic cardiomyopathy [163].

Compared with most lncRNAs, H19 is a locus with a high degree of sequence conservation in mammals, which means that H19 has important functions and may be a potential therapeutic possibility as a targeting molecule in HCM.

Overexpression of H19 could reduce cardiomyocyte size in response to phenylephrine [67]. Moreover, to evaluate the effect of H19 on myocardium, Viereck et al. established a cardiomyocyte-specific H19 gene therapy approach [68]. These authors used cardiomyocyte-related adeno-associated virus 9 (AAV9) as a vector and the cardiomyocyte-specific TNNT2 promoter to inhibit H19 expression in cardiomyocytes. Interestingly, echocardiography assessment showed that both murine and human H19 overexpression stall hypertrophy progression. These findings indicate that H19 is highly conserved and dysregulated in hypertrophic hearts of pigs and humans. This emphasizes that H19 is a promising therapeutic target for pathological CH.

All these studies show that lncRNAs play a crucial role in the occurrence and progression of heart disease and will become a new hot spot and focus of cardiovascular basic and clinical research. Regulation of H19 expression provides a new direction for future treatment of CH. However, further research is warranted to clarify the following issues: (i) What processes regulates the H19 levels in the oncogenesis, development, and progression of CH? (ii) Accumulating data suggest that H19 is expressed in almost every human cancer [164, 165], so could H19 lead to unpredictable toxicity and side effects during the process of influencing CH? (iii) How does H19 participate in different pathways to regulate CH? (iv) Does H19 act on both myocardial cells and fibroblasts to regulate myocardial hypertrophy? (v) What are other H19 targets involved in regulating CH? Therefore, further research is needed to understand the functions of H19 that are widely involved in cardiac homeostasis, diseases and therapeutics, but toxic effects and other side effects must be considered.

Outlook

Increasing evidence illustrated that H19, by acting as a molecular sponge or interacting with various proteins to regulate gene expression, could play an essential role in the complex network that regulates pathological hypertrophy progression, which includes intracellular calcium transition, fibrosis, angiogenesis, etc. These results indicate that H19 is a potential marker or a promising target for the treatment of CH. Nevertheless, there are still some questions to answer about the pathological mechanisms of CH. Thus, it is desirable to explore the molecular mechanisms and cellular pathways controlled by H19 in CH.

Availability of data and materials

Not applicable.

References

  1. Maron BJ, Doerer JJ, Haas TS, et al. Sudden deaths in young competitive athletes: analysis of 1866 deaths in the United States, 1980–2006. Circulation. 2009;119(8):1085–92.

    Article  PubMed  Google Scholar 

  2. Maron BJ, Gardin JM, Flack JM, et al. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA study. Coronary Artery Risk Development in (young) Adults. Circulation. 1995;92(4):785–9.

    Article  CAS  PubMed  Google Scholar 

  3. Semsarian C, Ingles J, Maron MS, et al. New perspectives on the prevalence of hypertrophic cardiomyopathy. J Am Coll Cardiol. 2015;65(12):1249–54.

    Article  PubMed  Google Scholar 

  4. Frey N, Olson EN. Cardiac hypertrophy: the good, the bad, and the ugly. Annu Rev Physiol. 2003;65:45–79.

    Article  CAS  PubMed  Google Scholar 

  5. McCurdy J, Manor W. Four legged medicine: pets making hospital calls comfort their ailing owners. Pa Nurse. 1989;44(5):12, 19.

    CAS  PubMed  Google Scholar 

  6. Nakamura M, Sadoshima J. Mechanisms of physiological and pathological cardiac hypertrophy. Nat Rev Cardiol. 2018;15(7):387–407.

    Article  CAS  PubMed  Google Scholar 

  7. Hill JA, Olson EN. Cardiac plasticity. N Engl J Med. 2008;358(13):1370–80.

    Article  CAS  PubMed  Google Scholar 

  8. Harvey PA, Leinwand LA. The cell biology of disease: cellular mechanisms of cardiomyopathy. J Cell Biol. 2011;194(3):355–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Maillet M, van Berlo JH, Molkentin JD. Molecular basis of physiological heart growth: fundamental concepts and new players. Nat Rev Mol Cell Biol. 2013;14(1):38–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Tham YK, Bernardo BC, Ooi JY, et al. Pathophysiology of cardiac hypertrophy and heart failure: signaling pathways and novel therapeutic targets. Arch Toxicol. 2015;89(9):1401–38.

    Article  CAS  PubMed  Google Scholar 

  11. Shimizu I, Minamino T. Physiological and pathological cardiac hypertrophy. J Mol Cell Cardiol. 2016;97:245–62.

    Article  CAS  PubMed  Google Scholar 

  12. Benjamin EJ, Virani SS, Callaway CW, et al. Heart disease and stroke statistics-2018 update: a report from the american heart association. Circulation. 2018;137(12):e67-492.

    Article  PubMed  Google Scholar 

  13. Ritterhoff J, Young S, Villet O, et al. Metabolic remodeling promotes cardiac hypertrophy by directing glucose to aspartate biosynthesis. Circ Res. 2020;126(2):182–96.

    Article  CAS  PubMed  Google Scholar 

  14. Harada M, Luo X, Murohara T, et al. MicroRNA regulation and cardiac calcium signaling: role in cardiac disease and therapeutic potential. Circ Res. 2014;114(4):689–705.

    Article  CAS  PubMed  Google Scholar 

  15. Seok H, Lee H, Lee S, et al. Position-specific oxidation of miR-1 encodes cardiac hypertrophy. Nature. 2020;584(7820):279–85.

    Article  CAS  PubMed  Google Scholar 

  16. Robson A. Oxidation of miRNAs by ROS leads to cardiac hypertrophy. Nat Rev Cardiol. 2020;17(11):678.

    Article  CAS  PubMed  Google Scholar 

  17. Frieler RA, Mortensen RM. Immune cell and other noncardiomyocyte regulation of cardiac hypertrophy and remodeling. Circulation. 2015;131(11):1019–30.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Zhang Y, Huang Z, Li H. Insights into innate immune signalling in controlling cardiac remodelling. Cardiovasc Res. 2017;113(13):1538–50.

    Article  CAS  PubMed  Google Scholar 

  19. Zeitz MJ, Smyth JW. Translating translation to mechanisms of cardiac hypertrophy. J Cardiovasc Dev Dis. 2020. https://doi.org/10.3390/jcdd7010009.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Greco CM, Condorelli G. Epigenetic modifications and noncoding RNAs in cardiac hypertrophy and failure. Nat Rev Cardiol. 2015;12(8):488–97.

    Article  CAS  PubMed  Google Scholar 

  21. Wang Z, Zhang XJ, Ji YX, et al. The long noncoding RNA Chaer defines an epigenetic checkpoint in cardiac hypertrophy. Nat Med. 2016;22(10):1131–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bar C, Chatterjee S, Thum T. Long noncoding RNAs in cardiovascular pathology, diagnosis, and therapy. Circulation. 2016;134(19):1484–99.

    Article  PubMed  CAS  Google Scholar 

  23. Beermann J, Piccoli MT, Viereck J, et al. Non-coding RNAs in development and disease: background, mechanisms, and therapeutic approaches. Physiol Rev. 2016;96(4):1297–325.

    Article  CAS  PubMed  Google Scholar 

  24. Thum T, Condorelli G. Long noncoding RNAs and microRNAs in cardiovascular pathophysiology. Circ Res. 2015;116(4):751–62.

    Article  CAS  PubMed  Google Scholar 

  25. Rinn JL, Chang HY. Genome regulation by long noncoding RNAs. Annu Rev Biochem. 2012;81:145–66.

    Article  CAS  PubMed  Google Scholar 

  26. Da Sacco L, Baldassarre A, Masotti A. Bioinformatics tools and novel challenges in long non-coding RNAs (lncRNAs) functional analysis. Int J Mol Sci. 2012;13(1):97–114.

    Article  PubMed  CAS  Google Scholar 

  27. Shang D, Yang H, Xu Y, et al. A global view of network of lncRNAs and their binding proteins. Mol Biosyst. 2015;11(2):656–63.

    Article  CAS  PubMed  Google Scholar 

  28. Cai X, Cullen BR. The imprinted H19 noncoding RNA is a primary microRNA precursor. RNA. 2007;13(3):313–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang KC, Chang HY. Molecular mechanisms of long noncoding RNAs. Mol Cell. 2011;43(6):904–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gong C, Maquat LE. lncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3′ UTRs via Alu elements. Nature. 2011;470(7333):284–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Qi D, Wang M, Yu F. Knockdown of lncRNA-H19 inhibits cell viability, migration and invasion while promotes apoptosis via microRNA-143/RUNX2 axis in retinoblastoma. Biomed Pharmacother. 2019;109:798–805.

    Article  CAS  PubMed  Google Scholar 

  32. Kanduri C. Kcnq1ot1: a chromatin regulatory RNA. Semin Cell Dev Biol. 2011;22(4):343–50.

    Article  CAS  PubMed  Google Scholar 

  33. Fatica A, Bozzoni I. Long non-coding RNAs: new players in cell differentiation and development. Nat Rev Genet. 2014;15(1):7–21.

    Article  CAS  PubMed  Google Scholar 

  34. Ulitsky I, Bartel DP. lincRNAs: genomics, evolution, and mechanisms. Cell. 2013;154(1):26–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Flynn RA, Chang HY. Long noncoding RNAs in cell-fate programming and reprogramming. Cell Stem Cell. 2014;14(6):752–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Li YP, Duan FF, Zhao YT, et al. A TRIM71 binding long noncoding RNA Trincr1 represses FGF/ERK signaling in embryonic stem cells. Nat Commun. 2019;10(1):1368.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Guo CJ, Ma XK, Xing YH, et al. Distinct processing of lncRNAs contributes to non-conserved functions in stem cells. Cell. 2020;181(3):621–36.e22.

    Article  CAS  PubMed  Google Scholar 

  38. Das S, Zhang E, Senapati P, et al. A novel angiotensin II-induced long noncoding RNA giver regulates oxidative stress, inflammation, and proliferation in vascular smooth muscle cells. Circ Res. 2018;123(12):1298–312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sun L, Si M, Liu X, et al. Long-noncoding RNA Atrolnc-1 promotes muscle wasting in mice with chronic kidney disease. J Cachexia Sarcopenia Muscle. 2018;9(5):962–74.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Hudson WH, Prokhnevska N, Gensheimer J, et al. Expression of novel long noncoding RNAs defines virus-specific effector and memory CD8(+) T cells. Nat Commun. 2019;10(1):196.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Wang J, Xie S, Yang J, et al. The long noncoding RNA H19 promotes tamoxifen resistance in breast cancer via autophagy. J Hematol Oncol. 2019;12(1):81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kleaveland B, Shi CY, Stefano J, et al. A network of noncoding regulatory RNAs acts in the mammalian brain. Cell. 2018;174(2):350-62.e17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Mendell JT. Targeting a long noncoding RNA in breast cancer. N Engl J Med. 2016;374(23):2287–9.

    Article  PubMed  Google Scholar 

  44. Batista PJ, Chang HY. Long noncoding RNAs: cellular address codes in development and disease. Cell. 2013;152(6):1298–307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zhang X, Hong R, Chen W, et al. The role of long noncoding RNA in major human disease. Bioorg Chem. 2019;92:103214.

    Article  CAS  PubMed  Google Scholar 

  46. Klattenhoff CA, Scheuermann JC, Surface LE, et al. Braveheart, a long noncoding RNA required for cardiovascular lineage commitment. Cell. 2013;152(3):570–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Greco S, Salgado Somoza A, Devaux Y, et al. Long noncoding RNAs and cardiac disease. Antioxid Redox Signal. 2018;29(9):880–901.

    Article  CAS  PubMed  Google Scholar 

  48. Kurian L, Aguirre A, Sancho-Martinez I, et al. Identification of novel long noncoding RNAs underlying vertebrate cardiovascular development. Circulation. 2015;131(14):1278–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Sallam T, Jones M, Thomas BJ, et al. Transcriptional regulation of macrophage cholesterol efflux and atherogenesis by a long noncoding RNA. Nat Med. 2018;24(3):304–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Cremer S, Michalik KM, Fischer A, et al. Hematopoietic deficiency of the long noncoding RNA MALAT1 promotes atherosclerosis and plaque inflammation. Circulation. 2019;139(10):1320–34.

    Article  CAS  PubMed  Google Scholar 

  51. Huang Y, Wang L, Mao Y, et al. Long noncoding RNA-H19 contributes to atherosclerosis and induces ischemic stroke via the upregulation of acid phosphatase 5. Front Neurol. 2019;10:32.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Wang YN, Shan K, Yao MD, et al. Long noncoding RNA-GAS5: a novel regulator of hypertension-induced vascular remodeling. Hypertension. 2016;68(3):736–48.

    Article  CAS  PubMed  Google Scholar 

  53. Jin L, Lin X, Yang L, et al. AK098656, a novel vascular smooth muscle cell-dominant long noncoding RNA, promotes hypertension. Hypertension. 2018;71(2):262–72.

    Article  CAS  PubMed  Google Scholar 

  54. Zehendner CM, Valasarajan C, Werner A, et al. Long noncoding RNA TYKRIL plays a role in pulmonary hypertension via the p53-mediated regulation of PDGFRbeta. Am J Respir Crit Care Med. 2020. https://doi.org/10.1164/rccm.201910-2041OC.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Zhang Z, Gao W, Long QQ, et al. Increased plasma levels of lncRNA H19 and LIPCAR are associated with increased risk of coronary artery disease in a Chinese population. Sci Rep. 2017;7(1):7491.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Bitarafan S, Yari M, Broumand MA, et al. Association of increased levels of lncRNA H19 in PBMCs with risk of coronary artery disease. Cell J. 2019;20(4):564–8.

    PubMed  Google Scholar 

  57. Ponnusamy M, Liu F, Zhang YH, et al. Long noncoding RNA CPR (cardiomyocyte proliferation regulator) regulates cardiomyocyte proliferation and cardiac repair. Circulation. 2019;139(23):2668–84.

    Article  CAS  PubMed  Google Scholar 

  58. Omura J, Habbout K, Shimauchi T, et al. Identification of long noncoding RNA H19 as a new biomarker and therapeutic target in right ventricular failure in pulmonary arterial hypertension. Circulation. 2020;142(15):1464–84.

    Article  CAS  PubMed  Google Scholar 

  59. Lv L, Li T, Li X, et al. The lncRNA Plscr4 controls cardiac hypertrophy by regulating miR-214. Mol Ther Nucleic Acids. 2018;10:387–97.

    Article  CAS  PubMed  Google Scholar 

  60. Yu J, Yang Y, Xu Z, et al. Long noncoding RNA Ahit protects against cardiac hypertrophy through SUZ12 (suppressor of Zeste 12 protein homolog)-mediated downregulation of MEF2A (myocyte enhancer factor 2A). Circ Heart Fail. 2020;13(1):e006525.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Sun Y, Fan W, Xue R, et al. Transcribed ultraconserved regions, Uc.323, ameliorates cardiac hypertrophy by regulating the transcription of CPT1b (carnitine palmitoyl transferase 1b). Hypertension. 2020;75(1):79–90.

    Article  CAS  PubMed  Google Scholar 

  62. Cai B, Ma W, Ding F, et al. The long noncoding RNA CAREL controls cardiac regeneration. J Am Coll Cardiol. 2018;72(5):534–50.

    Article  PubMed  Google Scholar 

  63. Chen Y, Liu X, Chen L, et al. The long noncoding RNA XIST protects cardiomyocyte hypertrophy by targeting miR-330-3p. Biochem Biophys Res Commun. 2018;505(3):807–15.

    Article  CAS  PubMed  Google Scholar 

  64. Yan SM, Li H, Shu Q, et al. LncRNA SNHG1 exerts a protective role in cardiomyocytes hypertrophy via targeting miR-15a-5p/HMGA1 axis. Cell Biol Int. 2020;44(4):1009–19.

    Article  CAS  PubMed  Google Scholar 

  65. Xu Y, Luo Y, Liang C, et al. LncRNA-Mhrt regulates cardiac hypertrophy by modulating the miR-145a-5p/KLF4/myocardin axis. J Mol Cell Cardiol. 2020;139:47–61.

    Article  CAS  PubMed  Google Scholar 

  66. Han P, Li W, Lin CH, et al. A long noncoding RNA protects the heart from pathological hypertrophy. Nature. 2014;514(7520):102–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Liu L, An X, Li Z, et al. The H19 long noncoding RNA is a novel negative regulator of cardiomyocyte hypertrophy. Cardiovasc Res. 2016;111(1):56–65.

    Article  CAS  PubMed  Google Scholar 

  68. Thum T, Bär C, Engelhardt S, et al. Targeting muscle-enriched long non-coding RNA H19 reverses pathological cardiac hypertrophy. Eur Heart J. 2020. https://doi.org/10.1093/eurheartj/ehaa519.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Lai Y, He S, Ma L, et al. HOTAIR functions as a competing endogenous RNA to regulate PTEN expression by inhibiting miR-19 in cardiac hypertrophy. Mol Cell Biochem. 2017;432(1–2):179–87.

    Article  CAS  PubMed  Google Scholar 

  70. Zhang Q, Wang F, Wang F, et al. Long noncoding RNA MAGI1-IT1 regulates cardiac hypertrophy by modulating miR-302e/DKK1/Wnt/beta-catenin signaling pathway. J Cell Physiol. 2020;235(1):245–53.

    Article  CAS  PubMed  Google Scholar 

  71. Zou X, Wang J, Tang L, et al. LncRNA TUG1 contributes to cardiac hypertrophy via regulating miR-29b-3p. In Vitro Cell Dev Biol Anim. 2019;55(7):482–90.

    Article  CAS  PubMed  Google Scholar 

  72. Wang W, Wu C, Ren L, et al. MiR-30e-5p is sponged by Kcnq1ot1 and represses Angiotensin II-induced hypertrophic phenotypes in cardiomyocytes by targeting ADAM9. Exp Cell Res. 2020;394(2):112140.

    Article  CAS  PubMed  Google Scholar 

  73. Xu L, Wang H, Jiang F, et al. LncRNA AK045171 protects the heart from cardiac hypertrophy by regulating the SP1/MG53 signalling pathway. Aging. 2020;12(4):3126–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Viereck J, Kumarswamy R, Foinquinos A, et al. Long noncoding RNA Chast promotes cardiac remodeling. Sci Transl Med. 2016;8(326):326ra322.

    Article  CAS  Google Scholar 

  75. Zhang J, Liang Y, Huang X, et al. STAT3-induced upregulation of lncRNA MEG3 regulates the growth of cardiac hypertrophy through miR-361-5p/HDAC9 axis. Sci Rep. 2019;9(1):460.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Frey N, McKinsey TA, Olson EN. Decoding calcium signals involved in cardiac growth and function. Nat Med. 2000;6(11):1221–7.

    Article  CAS  PubMed  Google Scholar 

  77. Xiao L, Gu Y, Sun Y, et al. The long noncoding RNA XIST regulates cardiac hypertrophy by targeting miR-101. J Cell Physiol. 2019;234(8):13680–92.

    Article  CAS  PubMed  Google Scholar 

  78. Wang K, Liu F, Zhou LY, et al. The long noncoding RNA CHRF regulates cardiac hypertrophy by targeting miR-489. Circ Res. 2014;114(9):1377–88.

    Article  CAS  PubMed  Google Scholar 

  79. Wo Y, Guo J, Li P, et al. Long non-coding RNA CHRF facilitates cardiac hypertrophy through regulating Akt3 via miR-93. Cardiovasc Pathol. 2018;35:29–36.

    Article  PubMed  CAS  Google Scholar 

  80. Wang Y, Cao R, Yang W, et al. SP1-SYNE1-AS1-miR-525-5p feedback loop regulates Ang-II-induced cardiac hypertrophy. J Cell Physiol. 2019;234(8):14319–29.

    Article  CAS  PubMed  Google Scholar 

  81. Li C, Zhou G, Feng J, et al. Upregulation of lncRNA VDR/CASC15 induced by facilitates cardiac hypertrophy through modulating miR-432-5p/TLR4 axis. Biochem Biophys Res Commun. 2018;503(4):2407–14.

    Article  CAS  PubMed  Google Scholar 

  82. Li Z, Liu Y, Guo X, et al. Long noncoding RNA myocardial infarctionassociated transcript is associated with the microRNA1505p/P300 pathway in cardiac hypertrophy. Int J Mol Med. 2018;42(3):1265–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Long Y, Wang L, Li Z. SP1-induced SNHG14 aggravates hypertrophic response in in vitro model of cardiac hypertrophy via up-regulation of PCDH17. J Cell Mol Med. 2020;24(13):7115–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Wang D, Lin B, Zhang W, et al. Up-regulation of SNHG16 induced by CTCF accelerates cardiac hypertrophy by targeting miR-182-5p/IGF1 axis. Cell Biol Int. 2020;44(7):1426–35.

    Article  CAS  PubMed  Google Scholar 

  85. Wen ZQ, Li SH, Shui X, et al. LncRNA PEG10 aggravates cardiac hypertrophy through regulating HOXA9. Eur Rev Med Pharmacol Sci. 2019;23(3 Suppl):281–6.

    PubMed  Google Scholar 

  86. Jiang F, Zhou X, Huang J. Long non-coding RNA-ROR mediates the reprogramming in cardiac hypertrophy. PLoS One. 2016;11(4):e0152767.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Taniguchi T, Sullivan MJ, Ogawa O, et al. Epigenetic changes encompassing the IGF2/H19 locus associated with relaxation of IGF2 imprinting and silencing of H19 in Wilms tumor. Proc Natl Acad Sci USA. 1995;92(6):2159–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Gabory A, Ripoche MA, Le Digarcher A, et al. H19 acts as a trans regulator of the imprinted gene network controlling growth in mice. Development. 2009;136(20):3413–21.

    Article  CAS  PubMed  Google Scholar 

  89. Hurst LD, Smith NG. Molecular evolutionary evidence that H19 mRNA is functional. Trends Genet. 1999;15(4):134–5.

    Article  CAS  PubMed  Google Scholar 

  90. Zhou J, Xu J, Zhang L, et al. Combined single-cell profiling of lncRNAs and functional screening reveals that H19 is pivotal for embryonic hematopoietic stem cell development. Cell Stem Cell. 2019;24(2):285-98 e285.

    Article  CAS  PubMed  Google Scholar 

  91. Wan P, Su W, Zhang Y, et al. LncRNA H19 initiates microglial pyroptosis and neuronal death in retinal ischemia/reperfusion injury. Cell Death Differ. 2020;27(1):176–91.

    Article  CAS  PubMed  Google Scholar 

  92. Yu JL, Li C, Che LH, et al. Downregulation of long noncoding RNA H19 rescues hippocampal neurons from apoptosis and oxidative stress by inhibiting IGF2 methylation in mice with streptozotocin-induced diabetes mellitus. J Cell Physiol. 2019;234(7):10655–70.

    Article  CAS  PubMed  Google Scholar 

  93. Li DY, Busch A, Jin H, et al. H19 induces abdominal aortic aneurysm development and progression. Circulation. 2018;138(15):1551–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Fan W, Peng Y, Liang Z, et al. A negative feedback loop of H19/miR-675/EGR1 is involved in diabetic nephropathy by downregulating the expression of the vitamin D receptor. J Cell Physiol. 2019;234(10):17505–13.

    Article  CAS  PubMed  Google Scholar 

  95. Yamamoto Y, Nishikawa Y, Tokairin T, et al. Increased expression of H19 non-coding mRNA follows hepatocyte proliferation in the rat and mouse. J Hepatol. 2004;40(5):808–14.

    Article  CAS  PubMed  Google Scholar 

  96. Liu R, Li X, Zhu W, et al. Cholangiocyte-derived exosomal long noncoding RNA H19 promotes hepatic stellate cell activation and cholestatic liver fibrosis. Hepatology. 2019;70(4):1317–35.

    Article  CAS  PubMed  Google Scholar 

  97. Hao Y, Crenshaw T, Moulton T, et al. Tumour-suppressor activity of H19 RNA. Nature. 1993;365(6448):764–7.

    Article  CAS  PubMed  Google Scholar 

  98. Zhang J, Han C, Ungerleider N, et al. A transforming growth factor-beta and H19 signaling axis in tumor-initiating hepatocytes that regulates hepatic carcinogenesis. Hepatology. 2019;69(4):1549–63.

    Article  CAS  PubMed  Google Scholar 

  99. El Hajj J, Nguyen E, Liu Q, et al. Telomerase regulation by the long non-coding RNA H19 in human acute promyelocytic leukemia cells. Mol Cancer. 2018;17(1):85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Geng H, Bu HF, Liu F, et al. In inflamed intestinal tissues and epithelial cells, interleukin 22 signaling increases expression of H19 long noncoding RNA, which promotes mucosal regeneration. Gastroenterology. 2018;155(1):144–55.

    Article  CAS  PubMed  Google Scholar 

  101. Cai B, Ma W, Bi C, et al. Long noncoding RNA H19 mediates melatonin inhibition of premature senescence of c-kit(+) cardiac progenitor cells by promoting miR-675. J Pineal Res. 2016;61(1):82–95.

    Article  CAS  PubMed  Google Scholar 

  102. Liu Z, Liu L, Zhong Y, et al. LncRNA H19 over-expression inhibited Th17 cell differentiation to relieve endometriosis through miR-342-3p/IER3 pathway. Cell Biosci. 2019;9:84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Hofmann P, Sommer J, Theodorou K, et al. Long non-coding RNA H19 regulates endothelial cell aging via inhibition of STAT3 signalling. Cardiovasc Res. 2019;115(1):230–42.

    Article  CAS  PubMed  Google Scholar 

  104. Hadji F, Boulanger MC, Guay SP, et al. Altered DNA methylation of long noncoding RNA H19 in calcific aortic valve disease promotes mineralization by silencing NOTCH1. Circulation. 2016;134(23):1848–62.

    Article  CAS  PubMed  Google Scholar 

  105. Li X, Luo S, Zhang J, et al. lncRNA H19 alleviated myocardial I/RI via suppressing miR-877-3p/Bcl-2-mediated mitochondrial apoptosis. Mol Ther Nucleic Acids. 2019;17:297–309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Wang JX, Zhang XJ, Li Q, et al. MicroRNA-103/107 regulate programmed necrosis and myocardial ischemia/reperfusion injury through targeting FADD. Circ Res. 2015;117(4):352–63.

    Article  CAS  PubMed  Google Scholar 

  107. Yang Y, Tang F, Wei F, et al. Silencing of long non-coding RNA H19 downregulates CTCF to protect against atherosclerosis by upregulating PKD1 expression in ApoE knockout mice. Aging. 2019;11(22):10016–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Greco S, Zaccagnini G, Perfetti A, et al. Long noncoding RNA dysregulation in ischemic heart failure. J Transl Med. 2016;14(1):183.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Eisner DA, Caldwell JL, Kistamas K, et al. Calcium and excitation-contraction coupling in the heart. Circ Res. 2017;121(2):181–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Bers DM. Cardiac excitation-contraction coupling. Nature. 2002;415(6868):198–205.

    Article  CAS  PubMed  Google Scholar 

  111. Toko H, Takahashi H, Kayama Y, et al. Ca2+/calmodulin-dependent kinase IIdelta causes heart failure by accumulation of p53 in dilated cardiomyopathy. Circulation. 2010;122(9):891–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Junho CVC, Trentin-Sonoda M, Alvim JM, et al. Ca2+/Calmodulin-dependent kinase II delta B is essential for cardiomyocyte hypertrophy and complement gene expression after LPS and HSP60 stimulation in vitro. Braz J Med Biol Res. 2019;52(7):e8732.

    Article  CAS  Google Scholar 

  113. Nassal D, Gratz D, Hund TJ. Challenges and opportunities for therapeutic targeting of calmodulin kinase II in heart. Front Pharmacol. 2020;11:35.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Helms AS, Alvarado FJ, Yob J, et al. Genotype-dependent and -independent calcium signaling dysregulation in human hypertrophic cardiomyopathy. Circulation. 2016;134(22):1738–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Zhu M, Chen Q, Liu X, et al. lncRNA H19/miR-675 axis represses prostate cancer metastasis by targeting TGFBI. FEBS J. 2014;281(16):3766–75.

    Article  CAS  PubMed  Google Scholar 

  116. Keniry A, Oxley D, Monnier P, et al. The H19 lincRNA is a developmental reservoir of miR-675 that suppresses growth and Igf1r. Nat Cell Biol. 2012;14(7):659–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Zhang T, Maier LS, Dalton ND, et al. The deltaC isoform of CaMKII is activated in cardiac hypertrophy and induces dilated cardiomyopathy and heart failure. Circ Res. 2003;92(8):912–9.

    Article  CAS  PubMed  Google Scholar 

  118. Baltas LG, Karczewski P, Krause EG. The cardiac sarcoplasmic reticulum phospholamban kinase is a distinct delta-CaM kinase isozyme. FEBS Lett. 1995;373(1):71–5.

    Article  CAS  PubMed  Google Scholar 

  119. Hon GC, Rajagopal N, Shen Y, et al. Epigenetic memory at embryonic enhancers identified in DNA methylation maps from adult mouse tissues. Nat Genet. 2013;45(10):1198–206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Papait R, Cattaneo P, Kunderfranco P, et al. Genome-wide analysis of histone marks identifying an epigenetic signature of promoters and enhancers underlying cardiac hypertrophy. Proc Natl Acad Sci USA. 2013;110(50):20164–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Luo M, Li Z, Wang W, et al. Long non-coding RNA H19 increases bladder cancer metastasis by associating with EZH2 and inhibiting E-cadherin expression. Cancer Lett. 2013;333(2):213–21.

    Article  CAS  PubMed  Google Scholar 

  122. Kong P, Christia P, Frangogiannis NG. The pathogenesis of cardiac fibrosis. Cell Mol Life Sci. 2014;71(4):549–74.

    Article  CAS  PubMed  Google Scholar 

  123. Nunes MC, Guimaraes Junior MH, Diamantino AC, et al. Cardiac manifestations of parasitic diseases. Heart. 2017;103(9):651–8.

    Article  PubMed  Google Scholar 

  124. Wang X, Cheng Z, Dai L, et al. Knockdown of long noncoding RNA H19 Represses the progress of pulmonary fibrosis through the transforming growth factor beta/Smad3 pathway by regulating microRNA 140. Mol Cell Biol. 2019. https://doi.org/10.1128/MCB.00143-19.

    Article  PubMed  PubMed Central  Google Scholar 

  125. Choong OK, Chen CY, Zhang J, et al. Hypoxia-induced H19/YB-1 cascade modulates cardiac remodeling after infarction. Theranostics. 2019;9(22):6550–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Omura J, Habbout K, Shimauchi T, et al. Identification of long noncoding RNA H19 as a New biomarker and therapeutic target in right ventricular failure in pulmonary arterial hypertension. Circulation. 2020;142(15):1464–84.

    Article  CAS  PubMed  Google Scholar 

  127. Tao H, Cao W, Yang JJ, et al. Long noncoding RNA H19 controls DUSP5/ERK1/2 axis in cardiac fibroblast proliferation and fibrosis. Cardiovasc Pathol. 2016;25(5):381–9.

    Article  CAS  PubMed  Google Scholar 

  128. Huang ZW, Tian LH, Yang B, et al. Long noncoding RNA H19 acts as a competing endogenous RNA to mediate CTGF expression by sponging miR-455 in cardiac fibrosis. DNA Cell Biol. 2017;36(9):759–66.

    Article  CAS  PubMed  Google Scholar 

  129. Delgado-Olguin P, Huang Y, Li X, et al. Epigenetic repression of cardiac progenitor gene expression by Ezh2 is required for postnatal cardiac homeostasis. Nat Genet. 2012;44(3):343–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Oka T, Akazawa H, Naito AT, et al. Angiogenesis and cardiac hypertrophy: maintenance of cardiac function and causative roles in heart failure. Circ Res. 2014;114(3):565–71.

    Article  CAS  PubMed  Google Scholar 

  131. Hamasaki S, Al Suwaidi J, Higano ST, et al. Attenuated coronary flow reserve and vascular remodeling in patients with hypertension and left ventricular hypertrophy. J Am Coll Cardiol. 2000;35(6):1654–60.

    Article  CAS  PubMed  Google Scholar 

  132. Voellenkle C, Garcia-Manteiga JM, Pedrotti S, et al. Implication of Long noncoding RNAs in the endothelial cell response to hypoxia revealed by RNA-sequencing. Sci Rep. 2016;6:24141.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Zhu A, Chu L, Ma Q, et al. Long non-coding RNA H19 down-regulates miR-181a to facilitate endothelial angiogenic function. Artif Cells Nanomed Biotechnol. 2019;47(1):2698–705.

    Article  CAS  PubMed  Google Scholar 

  134. Sano M, Minamino T, Toko H, et al. p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload. Nature. 2007;446(7134):444–8.

    Article  CAS  PubMed  Google Scholar 

  135. Semenza GL. Hypoxia-inducible factor 1 and cardiovascular disease. Annu Rev Physiol. 2014;76:39–56.

    Article  CAS  PubMed  Google Scholar 

  136. Li X, Wang H, Yao B, et al. lncRNA H19/miR-675 axis regulates cardiomyocyte apoptosis by targeting VDAC1 in diabetic cardiomyopathy. Sci Rep. 2016;6:36340.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Hu Y, Li S, Zou Y. Knockdown of LncRNA H19 relieves LPS-Induced damage by modulating mir-130a in osteoarthritis. Yonsei Med J. 2019;60(4):381–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Swynghedauw B. Molecular mechanisms of myocardial remodeling. Physiol Rev. 1999;79(1):215–62.

    Article  CAS  PubMed  Google Scholar 

  139. Ayca B, Sahin I, Kucuk SH, et al. Increased transforming growth factor-beta levels associated with cardiac adverse events in hypertrophic cardiomyopathy. Clin Cardiol. 2015;38(6):371–7.

    Article  PubMed  PubMed Central  Google Scholar 

  140. Anthony SR, Guarnieri AR, Gozdiff A, et al. Mechanisms linking adipose tissue inflammation to cardiac hypertrophy and fibrosis. Clin Sci. 2019;133(22):2329–44.

    Article  CAS  Google Scholar 

  141. Higuchi Y, Otsu K, Nishida K, et al. Involvement of reactive oxygen species-mediated NF-kappa B activation in TNF-alpha-induced cardiomyocyte hypertrophy. J Mol Cell Cardiol. 2002;34(2):233–40.

    Article  CAS  PubMed  Google Scholar 

  142. Zhang C, Wang F, Zhang Y, et al. Celecoxib prevents pressure overload-induced cardiac hypertrophy and dysfunction by inhibiting inflammation, apoptosis and oxidative stress. J Cell Mol Med. 2016;20(1):116–27.

    Article  CAS  PubMed  Google Scholar 

  143. Yu B, Zhao Y, Zhang H, et al. Inhibition of microRNA-143-3p attenuates myocardial hypertrophy by inhibiting inflammatory response. Cell Biol Int. 2018;42(11):1584–93.

    Article  CAS  PubMed  Google Scholar 

  144. Sun Y, Zhong L, He X, et al. LncRNA H19 promotes vascular inflammation and abdominal aortic aneurysm formation by functioning as a competing endogenous RNA. J Mol Cell Cardiol. 2019;131:66–81.

    Article  CAS  PubMed  Google Scholar 

  145. Hayakawa Y, Chandra M, Miao W, et al. Inhibition of cardiac myocyte apoptosis improves cardiac function and abolishes mortality in the peripartum cardiomyopathy of Galpha(q) transgenic mice. Circulation. 2003;108(24):3036–41.

    Article  CAS  PubMed  Google Scholar 

  146. Hein S, Arnon E, Kostin S, et al. Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: structural deterioration and compensatory mechanisms. Circulation. 2003;107(7):984–91.

    Article  PubMed  Google Scholar 

  147. Pan JX. LncRNA H19 promotes atherosclerosis by regulating MAPK and NF-kB signaling pathway. Eur Rev Med Pharmacol Sci. 2017;21(2):322–8.

    PubMed  Google Scholar 

  148. Zhang L, Cheng H, Yue Y, et al. H19 knockdown suppresses proliferation and induces apoptosis by regulating miR-148b/WNT/beta-catenin in ox-LDL -stimulated vascular smooth muscle cells. J Biomed Sci. 2018;25(1):11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  149. Zhang Y, Zhang M, Xu W, et al. The long non-coding RNA H19 promotes cardiomyocyte apoptosis in dilated cardiomyopathy. Oncotarget. 2017;8(17):28588–94.

    Article  PubMed  PubMed Central  Google Scholar 

  150. Elliott P, McKenna WJ. Hypertrophic cardiomyopathy. Lancet. 2004;363(9424):1881–91.

    Article  CAS  PubMed  Google Scholar 

  151. Toischer K, Rokita AG, Unsold B, et al. Differential cardiac remodeling in preload versus afterload. Circulation. 2010;122(10):993–1003.

    Article  PubMed  PubMed Central  Google Scholar 

  152. Thiele H, Ohman EM, de Waha-Thiele S, et al. Management of cardiogenic shock complicating myocardial infarction: an update 2019. Eur Heart J. 2019;40(32):2671–83.

    Article  CAS  PubMed  Google Scholar 

  153. Houser SR. Does a newly characterized cell from the bone marrow repair the heart after acute myocardial infarction? Circ Res. 2018;122(8):1036–8.

    Article  CAS  PubMed  Google Scholar 

  154. Vausort M, Wagner DR, Devaux Y. Long noncoding RNAs in patients with acute myocardial infarction. Circ Res. 2014;115(7):668–77.

    Article  CAS  PubMed  Google Scholar 

  155. Han Y, Dong B, Chen M, et al. LncRNA H19 suppresses pyroptosis of cardiomyocytes to attenuate myocardial infarction in a PBX3/CYP1B1-dependent manner. Mol Cell Biochem. 2021;476(3):1387–400.

    Article  CAS  PubMed  Google Scholar 

  156. Zhang BF, Jiang H, Chen J, et al. LncRNA H19 ameliorates myocardial infarction-induced myocardial injury and maladaptive cardiac remodelling by regulating KDM3A. J Cell Mol Med. 2020;24(1):1099–115.

    Article  CAS  PubMed  Google Scholar 

  157. Zhang QJ, Tran TAT, Wang M, et al. Histone lysine dimethyl-demethylase KDM3A controls pathological cardiac hypertrophy and fibrosis. Nat Commun. 2018;9(1):5230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Chatterjee S, Bar C, Thum T. Linc-ing the noncoding genome to heart function: beating hypertrophy. Trends Mol Med. 2017;23(7):577–9.

    Article  CAS  PubMed  Google Scholar 

  159. Gomez J, Lorca R, Reguero JR, et al. Genetic variation at the long noncoding RNA H19 gene is associated with the risk of hypertrophic cardiomyopathy. Epigenomics. 2018;10(7):865–73.

    Article  CAS  PubMed  Google Scholar 

  160. Strom CC, Aplin M, Ploug T, et al. Expression profiling reveals differences in metabolic gene expression between exercise-induced cardiac effects and maladaptive cardiac hypertrophy. FEBS J. 2005;272(11):2684–95.

    Article  CAS  PubMed  Google Scholar 

  161. Huynh K, Bernardo BC, McMullen JR, et al. Diabetic cardiomyopathy: mechanisms and new treatment strategies targeting antioxidant signaling pathways. Pharmacol Ther. 2014;142(3):375–415.

    Article  CAS  PubMed  Google Scholar 

  162. Song M, Franco A, Fleischer JA, et al. Abrogating mitochondrial dynamics in mouse hearts accelerates mitochondrial senescence. Cell Metab. 2017;26(6):872-83.e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Olivotto I, Oreziak A, Barriales-Villa R, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020;396(10253):759–69.

    Article  CAS  PubMed  Google Scholar 

  164. Lecerf C, Le Bourhis X, Adriaenssens E. The long non-coding RNA H19: an active player with multiple facets to sustain the hallmarks of cancer. Cell Mol Life Sci. 2019;76(23):4673–87.

    Article  CAS  PubMed  Google Scholar 

  165. Raveh E, Matouk IJ, Gilon M, et al. The H19 Long non-coding RNA in cancer initiation, progression and metastasis—a proposed unifying theory. Mol Cancer. 2015;14:184.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

Contract grant sponsor: Applied Basic Research Foundation of Yunnan Province (202001AY070001-286). Scientific Research Foundation of Education Department of Yunnan Province (2020Y0083). National Natural Science Foundation of China (81960065).

Author information

Author notes

  1. Wenhua Su and Qian Huo both contributed equally to this work and share first authorship

Authors and Affiliations

  1. Faculty of Life Science and Biotechnology, Kunming University of Science and Technology, 650500, Kunming, People’s Republic of China

    Wenhua Su, Lulin Wang, Juhua Dan & Hong Zhang

  2. Department of Cardiology, The First People’s Hospital of Yunnan Province, 650032, Kunming, People’s Republic of China

    Wenhua Su, Qian Huo, Hao Wu, Xiaoxue Ding, Liwen Liang, Liang Zhou, Yan Zhao & Hong Zhang

Authors
  1. Wenhua Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qian Huo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hao Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lulin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaoxue Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Liwen Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Liang Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yan Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Juhua Dan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ZH and JHD designed the study. WHS and QH collected materials and wrote the first draft of the manuscript. HW and LLW modified the manuscript and drew illustrations. XXD and LW provided essential suggestions for modifying the article. LZ helped generate the illustrations. YZ assisted in translating the manuscript. WHS, QH and JHD revised the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Juhua Dan or Hong Zhang.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

None of the authors has any conflicts of interest to disclose.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Su, W., Huo, Q., Wu, H. et al. The function of LncRNA-H19 in cardiac hypertrophy. Cell Biosci 11, 153 (2021). https://doi.org/10.1186/s13578-021-00668-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13578-021-00668-4

Keywords

Cell & Bioscience

ISSN: 2045-3701

Contact us