PPARs in atherosclerosis: The spatial and temporal features from mechanism to druggable targets

Abstract

Background: Atherosclerosis is a chronic and complex disease caused by lipid disorder, inflammation, and other factors. It is closely related to cardiovascular diseases, the chief cause of death globally. Peroxisome proliferator-activated receptors (PPARs) are valuable anti-atherosclerosis targets that showcase multiple roles at different pathological stages of atherosclerosis and for cell types at different tissue sites.

Aim of review: Considering the spatial and temporal characteristics of the pathological evolution of atherosclerosis, the roles and pharmacological and clinical studies of PPARs were summarized systematically and updated under different pathological stages and in different vascular cells of atherosclerosis. Moreover, selective PPAR modulators and PPAR-pan agonists can exert their synergistic effects meanwhile reducing the side effects, thereby providing novel insight into future drug development for precise spatial-temporal therapeutic strategy of anti-atherosclerosis targeting PPARs.

Key scientific: Concepts of Review: Based on the spatial and temporal characteristics of atherosclerosis, we have proposed the importance of stage- and cell type-dependent precision therapy. Initially, PPARs improve endothelial cells' dysfunction by inhibiting inflammation and oxidative stress and then regulate macrophages' lipid metabolism and polarization to improve fatty streak. Finally, PPARs reduce fibrous cap formation by suppressing the proliferation and migration of vascular smooth muscle cells (VSMCs). Therefore, research on the cell type-specific mechanisms of PPARs can provide the foundation for space-time drug treatment. Moreover, pharmacological studies have demonstrated that several drugs or compounds can exert their effects by the activation of PPARs. Selective PPAR modulators (that specifically activate gene subsets of PPARs) can exert tissue and cell-specific effects. Furthermore, the dual- or pan-PPAR agonist could perform a better role in balancing efficacy and side effects. Therefore, research on cells/tissue-specific activation of PPARs and PPAR-pan agonists can provide the basis for precision therapy and drug development of PPARs.

Keywords: Atherosclerosis; Endothelial cells; Macrophages; PPARs; Pharmacology; VSMCs.

Graphical abstract

Fig. 1

Schematic representation of the mechanism through which PPARs act on vascular endothelium. A The activation of endothelial cells. PPARs regulated the key molecules to reduce the secretion of adhesion molecules and proinflammatory cytokines. B Oxidative stress and NO. PPARs can reduce the superfluous ROS production and the activity of NADPH oxidase, which are both involved in the upregulation of the NO levels and NO bioavailability as well as the decrease in oxidative stress. C Aging and apoptosis. PPARα and PPARγ inhibit the related protein expression toward reducing cell aging and apoptosis. PPARδ activated by different ligands could exert promotional or inhibitory effects on apoptosis.

Fig. 2

Schematic representation of the mechanism through which PPARs act on macrophages. A The formation of foam cells. The processes of foam cell formation involve cholesterol uptake, esterification, and efflux. PPAR activation could increase the expression of receptors associated with cholesterol uptake such as CD36 and SR-A. However, the synthetic impact of PPAR activation is to promote cholesterol mobilization and efflux and reduce cholesterol storage, which is mainly characterized by upregulating the expressions of ABCA1, ABCG1, and SR-BI. B Polarization of macrophages. In classically activated M1 macrophages, PPARs activation could reduce the levels of proinflammatory molecules through the regulation of the key signaling pathways, such as AP-1, NF-κB, and AKT/FoxO1. However, PPARγ can significantly increase the CTRPs expression, which increases the levels of pro-atherogenic factors, including MCP-1, TNF-α, IL-1β, and IL-6. In M2 macrophages, PPARδ and PPARγ are involved in the transformation of macrophage M2 phenotypes.

Fig. 3

Schematic representation of the mechanism through which PPARs act on vascular smooth muscle cells. A Proliferation of VSMCs. PPARs mainly act to inhibit proliferation by targeting different proteins or signaling pathways. B Migration of VSMCs. PPAR activation inhibits the migration of cells from the media to the intima, which can decrease the formation of fibrous cap. C VSMC inflammation. PPAR activation can exert an anti-inflammatory effect by inhibiting the activity of NF-κB, AP-1, and TLR4 et al. D Apoptosis of VSMCs. PPAR activation can decrease the expression of several apoptosis markers, such as Bax, caspase-3, and caspase-9. E Vascular calcification. The activation of PPARγ regulates the expression of SFRP2, α-Klotho, and AT2 and inhibits RAAS to retard vascular calcification.