Peroxisome proliferator-activated receptors in the cardiovascular system

Abstract

Peroxisome proliferator-activated receptor (PPAR)s are a family of three nuclear hormone receptors, PPARalpha, -delta, and -gamma, which are members of the steriod receptor superfamily. The first member of the family (PPARalpha) was originally discovered as the mediator by which a number of xenobiotic drugs cause peroxisome proliferation in the liver. Defined functions for all these receptors, until recently, mainly concerned their ability to regulate energy balance, with PPARalpha being involved in beta-oxidation pathways, and PPARgamma in the differentiation of adipocytes. Little is known about the functions of PPARdelta, though it is the most ubiquitously expressed. Since their discovery, PPARs have been shown to be expressed in monocytes/macrophages, the heart, vascular smooth muscle cells, endothelial cells, and in atherosclerotic lesions. Furthermore, PPARs can be activated by a vast number of compounds including synthetic drugs, of the clofibrate, and anti-diabetic thiazoldinedione classes, polyunsaturated fatty acids, and a number of eicosanoids, including prostaglandins, lipoxygenase products, and oxidized low density lipoprotein. This review will aim to introduce the field of PPAR nuclear hormone receptors, and discuss the discovery and actions of PPARs in the cardiovascular system, as well as the source of potential ligands.

Figure 1

Activation of the PPAR receptors leads to an accumulation in the nucleus, where they heterodimerize with RXR. The PPAR : RXR heterodimer binds to DNA sequences called PPAR response elements (PPRE), leading to the transcription of the responsive gene. Activation of PPARα can cause peroxisome proliferation, and increased lipid metabolism; PPARγ causes cellular lipid accumulation in susceptible cells, and the down regulation of monocyte activation by cytokines; while the function of PPARδ is not known.

Figure 2

PPARα and PPARγ regulate vascular and inflammatory cell functions. Many different, often contradictory effects have been ascribed to PPAR ligands in vascular, and inflammatory cells. PPARα, and γ are expressed in endothelial cells, monocytes/macrophages, and in the vascular smooth muscle cells of both medial and intimal layers. PPARα ligands inhibit smooth muscle cell production of inflammatory products, and causes macrophage apoptosis. PPARγ ligands (i) inhibit smooth muscle cell migration processes; (ii) inhibit monocyte/macrophage production of inflammatory enzymes (iNOS; inducible nitric oxide synthase; Gel-B, gelatinase B), cytokines, and scavenger receptor (SR)-A expression; (iii) induce monocyte/macrophages differentiation, and uptake of oxidized LDL; (iv) induce monocyte and endothelial cell apoptosis; (v), inhibit the expression of vascular endothelial cell growth factor receptors, endothelin-1 and urokinase expression in endothelial cells and, (vi) induce plasminogen activator inhibitor-1 expression in endothelial cells.

Figure 3

PPAR ligands as products of cyclo-oxygenase (COX), lipoxygenase (LO), or oxidized low density lipoprotein (oxLDL). Little is actually known about which mediators act as true endogenous ligands, therefore the figure describes some of the potential pathways for the production of PPAR ligands. Directly binding PPAR ligands are noted in bold text. Constituitive (COX-1), or inducible (COX-2), present in vascular and inflammatory cells, can utilize primarily arachidonic acid to form PGH₂. PGH₂ is metabolized further to a number of prostanoid mediators, some of which, 15-deoxy-Δ^12,14-PGJ₂ (15d-PGJ₂, a dehydration product of PGD₂), PGA₂ (dehydration product of PGE₂), and PGI₂ (prostacyclin) that activate PPAR receptors. 5-LO, present in leukocytes, forms from arachidonic acid 5-HpETE, the precursor for 5-HETE, which itself is the precursor for leukotrienes (LT)s, of which LTB₄ is also a PPAR(α) agonist. 12/15-LOs, whose presence is strongly implied in the pathogenesis of atherosclerosis can produce PPAR agonists from arachidonic acid, the 12- and 15-HETEs, and form linoleic acid, 9- and 13-HODE. Low density lipoprotein LDL, which contains a number of phospholipids (PL)s, triglycerides (TG)s, cholesterol, cholesterol esters, and fatty acids, can be directly oxidized by 12/15-LOs, to produce PPAR ligands including 9- and 13-HODE. Furthermore, these unstable lipid hydroperoxides, 9- and 13-HODE, and the 12- and 15-HETEs, may themselves directly contribute to oxidization of LDL through a non-enzymatic pathway.