Table 1 Summary of brain NR effects on cardiovascular function and underlying mechanisms
NR | Pharmaceutical study | Genetic study | Brain expression | Functional brain regions | Effects on CV function |
|---|---|---|---|---|---|
I. Brain NRs that regulate cardiovascular functions | |||||
ER | Yes | Yes | The olfactory bulb, cerebral cortex, septum, preoptic area, bed nucleus of the stria terminalis, amygdala, paraventricular hypothalamic nucleus, thalamus, ventral tegmental area, substantia nigra, dorsal raphe, locus coeruleus, and cerebellum | 1. The rostral ventrolateral medulla (RVLM) 2. The paraventricular nucleus of the hypothalamus (PVH) | 1. ERβ, instead of ERα, induced significant decrease in systemic arterial pressure (SAP) and the power density of the vasomotor components of SAP signals 2. Both PVH and RVLM ERβ, instead of ERα in these nuclei, contribute to the protective effects of estrogen against aldosterone-induced hypertension |
MR | Yes | Yes | The dorsal and ventral hippocampal CA1-4 pyramidal cell fields and the dentate gyrus, amygdala, and lateral septum | NTS and projection neurons | MR-NTS regulates salt appetite and projection neurons including parabrachial nucleus, amygdala, paraventricular nucleus, hippocampus, and the bed nucleus of the striae terminalis (BNST) signal salt satiation |
THR | No | Yes | In mice, THRα1 mRNA is predominantly expressed in the heart and brain, whereas THRβ1 is expressed in peripheral tissue | Parvalbuminergic neurons in the anterior hypothalamus | THR in parvalbuminergic neurons is required for proper heart rate and blood pressure |
II. NRs that regulate cardiovascular functions with unclear brain connection | |||||
ERR | Yes | Yes | ERRα and ERRγ are both widely expressed in the brain, whereas ERRβ expression is restricted to the hindbrain | Unclear | ERRα and γ in heart after birth are required for normal cardiovascular function; ERRβ is involved in maintaining maximal ATP generation in contracting cardiomyocytes |
AR | No | Yes | The bed nucleus of the stria terminalis, lateral septum, medial amygdala, medial preoptic area, and ventromedial hypothalamic nucleus | Unclear | The androgen-AR system regulates normal cardiac growth, cardiac adaptive hypertrophy, and fibrosis during the process of cardiac remodeling under hypertrophic stress |
GR | Yes | Yes | The hippocampus and NTS | Unclear | Glucocorticoid administration increases blood pressure and contributes to the exacerbation of a cluster of cardiovascular risk factors |
PPAR | Yes | Yes | PPARα and PPARβ/δ mRNA and protein are found to express in prefrontal cortex, nucleus accumbens, amygdala and ventral tegmental area; PPARγ immunoreactivity was primarily observed in hypothalamic arcuate and ventromedial neurons and was also present in the hypothalamic paraventricular nucleus, the lateral hypothalamic area, and tyrosine hydroxylase-containing neurons in the ventral tegmental area | Unclear | Like PPARα, PPARβ/δ improves cardiac function and ameliorate the pathological progression of cardiac hypertrophy, heart failure, cardiac oxidative damage, ischemia–reperfusion injury, lipotoxic cardiac dysfunction and lipid-induced cardiac inflammation |
PR | Yes | Yes | Hypothalamic arcuate nucleus and anteroventral periventricular nucleus, hippocampus, and cortex | Unclear | Progesterone exhibits beneficial effects on the cardiovascular function such as lowers blood pressure, inhibits coronary hyperactivity, and has powerful vasodilatory and natriuretic effects |
RAR | Yes | Yes | RARα is found in cortex and hippocampus and RARβ and RXRγ are both highly expressed in the dopamine-innervated areas caudate/putamen, nucleus accumbens and olfactory tubercle | Unclear | RA carries out essential roles in heart development and after birth in the heart’s remodeling response to injury and disease |
RXR | No | Yes | Like above | Unclear | RAR/RXR regulates cardiovascular function including heart development, normal conductive system, and cardiac function |
ROR | Yes | Yes | RORα and γ are found in cerebellar cortex and other peripheral tissues while RORβ is found in pineal body | Unclear | RORs are critical in in the regulation of cardiovascular function including myocardial infarction, cardiac remodeling, etc |
VDR | Yes | Yes | The nucleus of tyrosine hydroxylase-positive neurons in both the human and rat substantia nigra | Unclear | Vitamin D deficiency in humans is associated with arterial stiffness, hypertension, left-ventricular hypertrophy, and endothelial dysfunction in patients with chronic kidney disease, as well as in normal subjects |
REV-ERB | Yes | Yes | Hippocampus, cortex, cerebellum, nigra, striatum, and hypothalamus | Unclear | REV-ERBα/β controls the progression of myocardial infarction and heart failure |
FXR | No | Yes | Frontal cortex and hippocampus | Unclear | FXR is expressed in cardiomyocytes and endothelial cells and acts as a novel functional receptor in cardiac tissue, regulates apoptosis in cardiomyocytes, and contributes to myocardial ischemia/reperfusion injury |
LXR | Yes | Yes | Hypothalamus, PVH | Unclear | LXRs exerts protective effects in the development of atherosclerosis and subsequent myocardial infarction and systolic heart failure |
SHP | No | Yes | Unclear | Unclear | SHP is required for normal cardiovascular function |
CAR | No | No | The cerebral cortex, hippocampus, amygdala, hypothalamus, and the basal ganglia | Unclear | CAR interacts with hypoxia inductile factor to regulate the hypoxia signaling for the development of cardiovascular disease |
SF-1 | Yes | Yes | Ventromedial hypothalamic nucleus (VMH) | VMH | Lesions in the VMH showed reduced sympathetic outflow and heart rate; VMH activation by electronic stimulation or drug injection could increase the SNS activity |
LRH-1 | No | Yes | Kisspeptin neurons in the arcuate nucleus | Unclear | LRH-1 directly regulates ApoA1 and decreased ApoA1 is associated with increased cardiovascular disease |
III. NRs without known cardiovascular functions | |||||
NGF1B | Yes | Yes | Hypothalamus and hippocampus | Unclear | Unclear |
GCNF | No | Yes | The developing nervous system, placenta, embryonic gonads, and adult ovaries and testes | Unclear | Unclear |
TR | No | No | the developing olfactory epithelium and in more caudal regions of the brain, including the cortex, ventral forebrain structures, and thalamus | Unclear | Unclear |
PXR | No | Yes | Unclear | Unclear | Unclear |
COUP-TF | No | No | POA-derived neurons | Unclear | Unclear |
DAX-1 | No | No | Hypothalamus | Unclear | Unclear |
TLX | No | No | Striatum, cortex, and hippocampus | Unclear | Unclear |
PNR | No | No | Unclear | Unclear | Unclear |
HNF4 | No | No | Unclear | Unclear | Unclear |