Abstract-Activation of nuclear hormone receptor peroxisome proliferator-activated receptor /␦ (PPAR) has been shown to improve insulin resistance and plasma high-density lipoprotein levels, but nothing is known about its effects in genetic hypertension. We studied whether the PPAR agonist GW0742 might exert antihypertensive effects in spontaneously hypertensive rats (SHRs). The rats were divided into 4 groups, Wistar Kyoto rat-control, Wistar Kyoto rat-treated (GW0742, 5 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 by oral gavage), SHR-control, and SHR-treated, and followed for 5 weeks. GW0742 induced a progressive reduction in systolic arterial blood pressure and heart rate in SHRs and reduced the mesenteric arterial remodeling, the increased aortic vasoconstriction to angiotensin II, and the endothelial dysfunction characteristic of SHRs. These effects were accompanied by a significant increase in endothelial NO synthase activity attributed to upregulated endothelial NO synthase and downregulated caveolin 1 protein expression. Moreover, GW0742 inhibited vascular superoxide production, downregulated p22 phox and p47 phox proteins, decreased both basal and angiotensin II-stimulated NADPH oxidase activity, inhibited extracellular-regulated kinase 1/2 activation, and reduced the expression of the proinflammatory and proatherogenic genes, interleukin 1, interleukin 6, or intercellular adhesion molecule 1. None of these effects were observed in Wistar Kyoto rats. PPAR activation, both in vitro and in vivo, increased the expression of the regulators of G protein-coupled signaling proteins RGS4 and RGS5, which negatively modulated the vascular actions of angiotensin II. PPAR activation exerted antihypertensive effects, restored the vascular structure and function, and reduced the oxidative, proinflammatory, and proatherogenic status of SHRs. We propose PPAR as a new therapeutic target in hypertension. T he peroxisome proliferator-activated receptors (PPARs) PPAR␣, PPAR/␦, and PPAR␥ are members of the nuclear hormone receptor superfamily. PPARs were initially believed to regulate genes involved only in lipid and glucose metabolism. 1 However, in recent years, evidence suggests that activation of PPAR␣ or PPAR␥ may exert cardiovascular protection beyond their metabolic effects. 2 In fact, PPAR␣ or PPAR␥ agonists exert antihypertensive effects in both human and animal models with or without metabolic disorders. [3][4][5][6] The mechanisms underlying the beneficial effects of PPARs beyond glucose and lipid metabolism may relate to their anti-inflammatory and antioxidant actions. 5 Thus, activation of both PPAR␣ or PPAR␥ antagonizes angiotensin II (Ang II) actions, including the activation of NADPH oxidase and the generation of reactive oxygen species, as well as the increase in proinflammatory mediators and adhesion molecules in blood vessels. 5,6 Activation of PPAR/␦ (PPAR) also exhibits antiinflammatory properties in the vessel wall by inhibiting the expression of vascular cell adhesion molecule 1 and monocyte chemoattractant prote...
