Untangling the Cooperative Role of Nuclear Receptors in Cardiovascular Physiology and Disease

Abstract

The heart is the first organ to acquire its physiological function during development, enabling it to supply the organism with oxygen and nutrients. Given this early commitment, cardiomyocytes were traditionally considered transcriptionally stable cells fully committed to contractile function. However, growing evidence suggests that the maintenance of cardiac function in health and disease depends on transcriptional and epigenetic regulation. Several studies have revealed that the complex transcriptional alterations underlying cardiovascular disease (CVD) manifestations such as myocardial infarction and hypertrophy is mediated by cardiac retinoid X receptors (RXR) and their partners. RXRs are members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors and drive essential biological processes such as ion handling, mitochondrial biogenesis, and glucose and lipid metabolism. RXRs are thus attractive molecular targets for the development of effective pharmacological strategies for CVD treatment and prevention. In this review, we summarize current knowledge of RXR partnership biology in cardiac homeostasis and disease, providing an up-to-date view of the molecular mechanisms and cellular pathways that sustain cardiomyocyte physiology.

Epigenetic State Changes Underlie Metabolic Switch in Mouse Post-Infarction Border Zone Cardiomyocytes

“…In addition, we observed decreased acetylation of motifs recognized by the nuclear receptor (NR) superfamily of transcription factors, including estrogen related receptor alpha (Erra), retinoid X receptor (RXR) and elements for peroxisome proliferator-activated receptors (PPARs). These transcription factors are involved in the regulation of fatty acid metabolism and oxidative phosphorylation [25,26]. We obtained similar results for the population displaying a decrease in H3K27ac as well as diminished chromatin accessibility (Figure 3D).…”

“…However, enhancers with decreased H3K27ac association were also enriched for motifs recognized by the NR superfamily of transcription factors, including peroxisome proliferator-activated receptors (PPARs) and retinoid X receptor (RXR). RXR forms heterodimers with PPARα to regulate the expression of genes involved in fatty acid oxidation, inflammation and apoptosis [24][25][26]. We found that RXR/PPARα target genes such as Cpt2 and Ech1 are significantly downregulated in BZ cardiomyocytes.…”

“…In the heart, fatty acid metabolism is regulated by peroxisome proliferator-activated receptors (PPAR), members of the NR superfamily of transcription factors [26,[64][65][66][67]. Conditions such as hypoxia were shown to lead to decreased PPARα expression and reduction of PPAR target gene expression causing cardiomyocytes to switch from fatty acid metabolism to glycolysis [67].…”

Adaptation of cardiomyogenesis to the generation and maturation of cardiomyocytes from human pluripotent stem cells

“…One important family is PPARs, activated by fatty acids and consisting of four members: PPARα, PPARβ, PPARγ, and PPARδ. In the heart, the most abundant is PPARα 60,150 . Studies show that PPARα and its coactivator PGC1α (peroxisome proliferator‐activated receptor gamma coactivator‐1α) regulate the expression of YAP and the splicing factors SF3B2/SAP18 151 .…”

“…In the heart, the most abundant is PPARα. 60,150 Studies show that PPARα and its coactivator PGC1α (peroxisome proliferator-activated receptor gamma coactivator-1α) regulate the expression of YAP and the splicing factors SF3B2/SAP18. 151 Yap has already been described as a regulator of cardiomyocyte hypertrophic growth, and inhibition of its activity dismissed the effects of activation of PPARα/PGC1α and reduced cardiomyocyte size.…”