Abstract
The nuclear receptor peroxisome proliferator-activated receptor δ (PPARδ) can transcriptionally regulate target genes. PPARδ exerts essential regulatory functions in the heart, which requires constant energy supply. PPARδ plays a key role in energy metabolism, controlling not only fatty acid (FA) and glucose oxidation, but also redox homeostasis, mitochondrial biogenesis, inflammation, and cardiomyocyte proliferation. PPARδ signaling is impaired in the heart under various pathological conditions, such as pathological cardiac hypertrophy, myocardial ischemia/reperfusion, doxorubicin cardiotoxicity and diabetic cardiomyopathy. PPARδ deficiency in the heart leads to cardiac dysfunction, myocardial lipid accumulation, cardiac hypertrophy/remodeling and heart failure. This article provides an up-today overview of this research area and discusses the role of PPARδ in the heart in light of the complex mechanisms of its transcriptional regulation and its potential as a translatable therapeutic target for the treatment of cardiac disorders.
Highlights
Peroxisome proliferator-activated receptors (PPARα, -γ and -δ) belong to a nuclear receptor transcription factor superfamily that regulates metabolic transcription
Several reports indicate that restoring peroxisome proliferator-activated receptor δ (PPARδ) protein expression in diabetic hearts from rats induced by STZ by various pharmacological compounds, such as histone deacetylase (HDAC) inhibitor [56], ginseng [9, 57] and ramipril [58]
We showed that a PPARδ-selective ligand, GW0742, inhibits the lipopolysaccharide (LPS)-induced transforming necrosis factor-α (TNF-α) production in cultured cardiomyocytes [87]
Summary
Peroxisome proliferator-activated receptors (PPARα, -γ and -δ) belong to a nuclear receptor transcription factor superfamily that regulates metabolic transcription. PPARs play essential roles in transcriptional regulation of many aspects of cellular metabolism, especially FAO. Several studies on cardiomyocyte-restricted PPARγ mice demonstrate its crucial role in cardiac physiology, probably via its role in transcriptionally regulating myocardial FA metabolism and anti-oxidant defense [14,15,16,17]. It becomes clear that all PPAR subtypes play roles in transcriptional regulation of myocardial energy and lipid homeostasis, but with differences in their cardiac expression levels and yet to defined differential regulation on various aspects of energy metabolism. Further studies on the potential distinctive roles of each PPAR subtype in the heart should provide new therapeutic targets for treating heart disease. We focus on summarizing the biological function and clinical implications of PPARδ in the heart
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