Trends in Molecular Medicine
ReviewThe role of PPARs in atherosclerosis
Section snippets
PPARs and the recruitment of leukocytes in the early atherosclerotic lesion
PPARs interfere with the earliest processes in atherogenesis, which consist of leukocyte chemoattraction and recruitment to atherosclerotic lesions. PPARs modulate the production of chemokines, the expression of chemokine receptors as well as adhesion molecules in endothelial cells (EC), T cells and monocytes. In ECs, glitazones inhibit the expression of the chemotactic protein monocyte-chemoattractant protein-1 (MCP-1) 8., 9.. Whereas PPARα agonists stimulate basal expression of MCP-1 by human
PPARs and local immune responses
Accumulating evidence indicates that the atherosclerotic process implicates a local immune response characterized by the recruitment, activation and proliferation of various cells of the immune system, including T cells and dendritic cells (DCs). In humans and murine models of atherosclerosis, the colocalization of activated T cells and DCs in atherosclerotic lesions suggests that cellular immunity plays an important role in the pathophysiology of this disease 28., 29.. It has been shown in
PPARs, lipid accumulation and reverse cholesterol transport
After recruitment in the subendothelial region of the artery, monocytes differentiate into macrophages and accumulate lipids to form foam cells. To enter macrophages, LDL must be modified (e.g. through oxidation or glycosylation). Reactive oxygen species (ROS) can induce the oxidative modification of LDL. Superoxide anion (O2·−) might furthermore promote atherogenesis by inducing hypertension and inflammation via NF-κB activation [25]. PPARα and γ activators increase the expression of the
PPARs and local inflammation
ECs, T cells, macrophages and SMCs are believed to contribute to the local inflammatory response by acquiring a pro-inflammatory phenotype. The effects of PPARγ ligands on the inflammation response of macrophages have been well studied, but the role of PPARγ therein is still under debate as the effects are most pronounced with the least selective and active PPARγ agonist, 15d-PGJ2 (reviewed in Ref. [52]) and are also observed in PPARδ-deficient mice [53]. The role of PPARα in inflammatory
PPARs and fibrous cap development
In middle-advanced stages of atherosclerosis, SMCs proliferate and produce extracellular matrix (ECM) components, thus leading to the formation of a fibrous plaque (fibroatheroma). PPARγ ligands inhibit the proliferation and the migration of vascular SMCs (VSMC), a phenomenon that might be of particular relevance for restenosis prevention 58., 59., 60.. Wakino et al. [61] have demonstrated that proliferation is inhibited most likely by blocking crucial events in G1→S transition, such as
PPARs and plaque stability
The evolution of atherosclerosis to thrombus-provoked coronary events principally depends on plaque stability. Unstable plaques are prone to rupture leading to thrombus formation and vessel wall occlusion. Maintenance of a stable fibrous cap mainly reflects a balance between ECM production and degradation. Troglitazone reduces gene expression of osteopontin, an ECM component synthesized by macrophages in atherosclerotic plaques [71]. Moreover, PPARα and γ ligands repress gene transcription 26.,
PPARs and thrombosis
PPARs also modulate platelet aggregation, an initiating event of atherothrombosis at the ruptured plaque. In rat macrophages, thromboxane synthase (TXS) is inhibited at the transcriptional level by PPARγ, interacting with the transcription factor NRF2 (nuclear factor-E2-related factor 2) [82]. In VSMCs, PPARγ activators inhibit expression of the thromboxane receptor (TXR) [66]. Thus, PPARγ activation results in a diminished synthesis and action of thromboxane A2, which is a potent inducer of
PPARs and acute-phase proteins
Acute-phase proteins are established risk factors for cardiovascular diseases. They are synthesized by the liver during the inflammation reaction. Fenofibrate significantly lowers plasma levels of C-reactive protein (CRP), a complement activator and an inducer of MCP-1 expression in ECs, and fibrinogen, a procoagulant factor [54]. In mice, fibrates decrease plasma fibrinogen levels in a PPARα-dependent manner [84]. PPARα activators repress human fibrinogen gene expression in human hepatocytes
Anti-atherosclerotic effects of PPARs: results from in vivo studies
Compelling evidence for a regulatory role for PPARs in atherogenesis in vivo comes from studies in animal models of atherosclerosis and human clinical trials. In different experimental models of atherosclerosis, PPARγ ligands prevent the progression of atherosclerotic lesions, with a concomitant decrease of macrophage accumulation in the plaque 15., 19., 87.. Glitazones act by reducing monocyte/macrophage homing to atherosclerotic plaques by inhibiting fatty streak formation, improving glucose
Concluding remarks
PPARs play a crucial role in lipid and lipoprotein metabolism as well as in glucose homeostasis. Considerable evidence indicates that PPARα and PPARγ have beneficial effects in inflammatory diseases, including atherosclerosis. These PPARs regulate cytokine production, adhesion molecule expression on endothelial cells, fibrinolysis and modulate macrophage functions. Interestingly, PPARβ/δ, whose function is still not well understood, has been recently implicated in the regulation of macrophage
Acknowledgements
C.D. was supported by a fellowship from ARC (Association pour la Recherche sur le Cancer) and G.C. was supported by grants from European Community (grant QLRT-1999–01007).
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2020, Biomedicine and PharmacotherapyCitation Excerpt :PPAR-γ has a variety of important physiological activities. PPAR-γ activation can promote the clearance of fatty acids, reduce the levels of TNF-α and leptin, down-regulate the expression of phosphodiesterase, and reduce blood glucose [41]. PPAR-γ activation can also promote the expression of GLUT4 and PI3K [42], ameliorate insulin signaling, and insulin resistance.