Peroxisome-proliferator-activated receptors regulate redox signaling in the cardiovascular system

Abstract

Peroxisome-proliferator-activated receptors (PPARs) comprise three subtypes (PPARα, δ and γ) to form a nuclear receptor superfamily. PPARs act as key transcriptional regulators of lipid metabolism, mitochondrial biogenesis, and anti-oxidant defense. While their roles in regulating lipid metabolism have been well established, the role of PPARs in regulating redox activity remains incompletely understood. Since redox activity is an integral part of oxidative metabolism, it is not surprising that changes in PPAR signaling in a specific cell or tissue will lead to alteration of redox state. The effects of PPAR signaling are directly related to PPAR expression, protein activities and PPAR interactions with their coregulators. The three subtypes of PPARs regulate cellular lipid and energy metabolism in most tissues in the body with overlapping and preferential effects on different metabolic steps depending on a specific tissue. Adding to the complexity, specific ligands of each PPAR subtype may also display different potencies and specificities of their role on regulating the redox pathways. Moreover, the intensity and extension of redox regulation by each PPAR subtype are varied depending on different tissues and cell types. Both beneficial and adverse effects of PPAR ligands against cardiovascular disorders have been extensively studied by many groups. The purpose of the review is to summarize the effects of each PPAR on regulating redox and the underlying mechanisms, as well as to discuss the implications in the cardiovascular system.

Keywords: Peroxisome-proliferator-activated receptor, Redox, Cardiovascular disorders, Oxidative stress, Antioxidant

Core tip: Numerous studies have shown that peroxisome-proliferator-activated receptors (PPARs) ligands can modulate antioxidants via various mechanisms. Importantly, direct transcriptional regulation of antioxidant genes, such as thioredoxin-1, glutathione peroxidase 3, sestrin-1, catalase, superoxide dismutase (SOD)1, SOD2, and heme oxygenase, is established by identifying functional PPAR responsive element in promoter regions of the above genes. This review summarizes how these important antioxidant genes are regulated by each subtype of PPARs in response to oxidative stress in the cardiovascular system and how oxidative stress affects PPAR function, as well as the biological implications in the cardiovascular system.