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.
Highlights
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 (Libby et al, 2016; Vallee et al, 2019; Machado-Oliveira et al, 2020)
Atherosclerosis is initiated by a large number of abnormally metabolized lipids including apolipoprotein B-containing lipoproteins continuously enter into the vascular intima to trigger an inflammatory response dominated by macrophages in the vascular wall (Chistiakov et al, 2015; Tabas, 2017), promote the migration and proliferation of vascular smooth muscle cells (VSMCs) (Durham et al, 2018), cause
PPARγ plays a crucial role in anti-atherosclerosis by promoting cholesterol efflux (Ozasa et al, 2011; Tsuboi et al, 2020), inhibiting monocytes infiltrating into the vascular intima under endothelial layer (Namgaladze et al, 2013), and inhibiting their transformation into macrophages (Zhang and Chawla, 2004; Charo, 2007; Oppi et al, 2020), inhibiting VSMCs proliferation and migration (Zhang et al, 2011; Durham et al, 2018)
Summary
Atherosclerosis is the hallmark of 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 (Libby et al, 2016; Vallee et al, 2019; Machado-Oliveira et al, 2020). One of TZDs’ major side effects is due to its activation of PPARγ in adipose tissue, and high-fat diet increased CDK5-mediated of PPARγ phosphorylation, which was negatively associated with TZDs’ insulin sensitization in humans.
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