ABSTRACT
Peroxisome proliferative-activated receptor agonists Activators of the ligand-activated nuclear transcription factor, peroxisome proliferator-activated receptor γ (PPARγ), have emerged as a promising target to modify vascular inflammation. PPARγ activators inhibit the release of proinflammatory cytokines and matrix-degrading enzymes in monocytes and macrophages; they modulate the expression of chemokines and endothelin in endothelial cells; and PPARγ ligands have been shown to reduce the secretion of interferon (IFN)-γ in T cells.97 In vascular smooth muscle cells, PPARγ activators decrease the release of MMPs. Because PPARγ can be activated by the novel group of clinically used antidiabetic thiazolidinediones (TZDs, glitazones),98 like troglitazone, rosiglitazone and pioglitazone, clinical data revealed a reduction of inflammatory serum markers of arteriosclerosis99 as well as a reduction of intima-media thickness upon TZD treatment in diabetic patients. PPARs also regulate chemoattraction and cellular adhesion to endothelial cells reducing cytokine-induced expression of VCAM-1 and ICAM-1.100,101 Incubation of human monocytes with natural prostaglandin (J2) and synthetic PPARγ ligands inhibits the production of inflammatory cytokines, such as TNF-α, IL-1β, IL-6, IL8 and IL-10.102-104 In vivo studies have demonstrated that troglitazone significantly reduced monocyte/macrophage recruitment to atherosclerotic lesions in apoE-null mice.105The atheroprotective role of PPARγ has been further documented in animal models of atherosclerosis.106 Similarly, rosiglitazone treatment of patients with type 2 diabetes significantly reduces plasma levels of IL-6 and CRP PPARγ activators inhibit the expression of MMP-9, a secreted MMP. PPAR agonists may also possess antithrombotic effects through several mechanisms including reduced platelet activation, tissue factor expression in lymphocytes and PAI-1107-114 which may prevent subsequent thrombosis (Box 14.2). Long-term clinical trials appear warranted.
