Role of Pleiotropic Properties of Peroxisome Proliferator‐Activated Receptors in the Heart: Focus on the Nonmetabolic Effects in Cardiac Protection

Abstract

SUMMARYPeroxisome proliferator-activated receptors, PPARa, PPARb/d, and PPARc, are a group of nuclear receptors that function as transcriptional regulators of lipid metabolism, energy homeostasis, and inflammation. Given the role of metabolism imbalance under pathological states of the heart, PPARs have emerged as important therapeutic targets, and accumulating evidence highlights their protective role in the improvement of cardiac function under diverse pathological settings. Although the role of PPARs in the regulation of cardiac substrate utilization preference and energy homeostasis is well documented, their effects related to the regulation of cellular inflammatory and redox responses in the heart are less studied. In this review, we provide an overview on recent progress with respect to understanding the role of the nonmetabolic effects of PPARs in cardiac dysfunction, namely during ischemia/reperfusion injury, hypertrophy, and cardiac failure, and highlight the mechanisms underlying the protective effects against inflammation, oxidative stress, and cell death. The role of receptor-independent, nongenomic effects of PPAR agonists is also discussed.

The Peroxisome-Mitochondria Connection: How and Why?

“…The expression of many genes involved in peroxisomal fatty acid β-oxidation and proliferation is controlled by transcription factors of the PPAR family [27,28,29]. PPARs (PPARα, PPARγ, and PPARδ) are ligand-activated nuclear receptors that act in concert with retinoid X receptors (RXRs) to regulate a variety of physiological processes (e.g., lipid and carbohydrate metabolism, cellular differentiation, and tumorigenesis) [28,30], and natural and synthetic PPAR agonists include dietary lipids and their metabolites, fibrates, and thiazolidines [31]. Each PPAR subtype displays a distinct tissue expression pattern and substrate specificity and regulates the expression of different target genes [32].…”

Targeting PPARα for the Treatment and Understanding of Cardiovascular Diseases

“…The cardiac-restricted overexpression of PPARα leads to impaired cardiac recovery after ischemia [84][85][86], and the use of the PPARα agonist WY-14643 during repetitive I/R results in the intramyocardial triglyceride (TG) accumulation, increased generation of reactive oxygen species (ROS), and subsequent enhancement of inflammation, apoptosis, and contractile dysfunction [87]. The detrimental effect of PPARα may be attributed to the increased production of ROS and lipotoxicity due to a switch of metabolism from glucose to FA utilization [88]. The contradictory results from cardiac-restricted PPARα overexpression and systemic PPARα activation in I/R heart models might be due to the effect of non-cardiac cells such as inflammatory cells.…”

Peroxisome Proliferator-Activated ReceptorαReduces Endothelin-1-Caused Cardiomyocyte Hypertrophy by Inhibiting Nuclear Factor-κB and Adiponectin

“…Activation of PPAR α reduces cardiac hypertrophy, decreases cardiac fibrosis, attenuates cardiac dysfunction, and improves survival by inhibition of profibrotic, proinflammatory, and prohypertrophic genes [6]. Fenofibrate, a PPAR α activator, has been reported to reduce ET-1-caused cardiac hypertrophy through downregulation of activating protein-1 (AP-1) binding and inhibition of p38 mitogen-activated protein kinases (MAPK) signaling [7, 8].…”