The Role of Peroxisome Proliferator-Activated Receptor Gamma and Atherosclerosis: Post-translational Modification and Selective Modulators

Abstract

Atherosclerosis is the hallmark of cardiovascular disease (CVD) which is a leading cause of death in type 2 diabetes patients, and glycemic control is not beneficial in reducing the potential risk of CVD. Clinically, it was shown that Thiazolidinediones (TZDs), a class of peroxisome proliferator-activated receptor gamma (PPARγ) agonists, are insulin sensitizers with reducing risk of CVD, while the potential adverse effects, such as weight gain, fluid retention, bone loss, and cardiovascular risk, restricts its use in diabetic treatment. PPARγ, a ligand-activated nuclear receptor, has shown to play a crucial role in anti-atherosclerosis by promoting cholesterol efflux, repressing monocytes infiltrating into the vascular intima under endothelial layer, their transformation into macrophages, and inhibiting vascular smooth muscle cells proliferation as well as migration. The selective activation of subsets of PPARγ targets, such as through PPARγ post-translational modification, is thought to improve the safety profile of PPARγ agonists. Here, this review focuses on the significance of PPARγ activity regulation (selective activation and post-translational modification) in the occurrence, development and treatment of atherosclerosis, and further clarifies the value of PPARγ as a safe therapeutic target for anti-atherosclerosis especially in diabetic treatment.

Keywords: PPARγ; atherosclerosis; cardiovascular disease; post-translational modifications; selective modulators.

FIGURE 1

PPARγ attenuated atherosclerosis through different aspects, including alleviating endothelial dysfunction, promoting cholesterol efflux, inducing M1-M2 transition, inhibiting VSMC migration and proliferation and stabilizing the fibrous cap and plaque.

FIGURE 2

Post-translational modification of PPARγ regulates atherosclerosis. (A) Both phosphorylation of PPARγ at S112 by CDK7/9 or MAPK and phosphorylation of PPARγ at S273 accelerates foam cell formation and atherosclerosis through different signaling pathway, some PPARγ agonist (WSF-7, SR1664) can block cdk5 mediated Ser273 phosphorylation. (B) Acetylation of PPARγ at K268/K293 increases atherosclerosis through upregulating ABCA1, ABCG1, and NcoR but inhibiting PRDM16,while deacetylation of PPARγ at K268 and K293 alleviates atherosclerosis, while PPARγ agonist rosiglitazone (Rosi) could deacetylate PPARγ at K268/K293. (C) Sumoylation of PPARγ at K107 promotes VSMCs proliferation and migration, but sumoylation of PPARγ at K395, such as by Rosi, has anti-inflammation effect.