Abstract-Rosiglitazone, a synthetic ligand of transcription factor peroxisome proliferator-activated receptor-␥ (PPAR-␥), possesses a blood pressure-lowering effect beyond insulin sensitizing and glucose lowering. Oxidative stress in rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons for the maintenance of neurogenic vasomotor tone are located, contributes to neural mechanisms of hypertension. Activation of PPAR-␥ protects against oxidative stress in RVLM by upregulation of mitochondrial uncoupling protein 2 (UCP2). We tested the hypothesis that oral intake of rosiglitazone exerts a central antihypertensive effect by ameliorating oxidative stress in RVLM via transcriptional upregulation of UCP2 after PPAR-␥ activation. In adult spontaneously hypertensive rats but not normotensive Wistar-Kyoto rats, oral intake of rosiglitazone for 1 week resulted in vasodepression and a reduction in the vasomotor components of the systemic arterial pressure spectrum, our experimental index for sympathetic vasomotor tone. These antihypertensive effects of rosiglitazone in spontaneously hypertensive rats were abrogated by microinjection bilaterally into RVLM of PPAR-␥ small interfering RNA. Oral intake of rosiglitazone also upregulated UCP2 and ameliorated the heightened superoxide anion level in RVLM of spontaneously hypertensive rats. Protection against oxidative stress in RVLM by rosiglitazone was abrogated by PPAR-␥ small interfering RNA or by antisense oligonucleotide against ucp2 mRNA. Gene knockdown of ucp2 in RVLM also reversed the antihypertensive effect of rosiglitazone. These results suggest that oral intake of rosiglitazone promotes a central antihypertensive effect by decreasing sympathetic vasomotor activity through a PPAR-␥-dependent protection against oxidative stress in RVLM via transcriptional upregulation of the mitochondrial UCP2. (Hypertension. 2010;55:1444-1453.)Key Words: peroxisome proliferator-activated receptor Ⅲ thiazolidinedione Ⅲ mitochondrial uncoupling protein Ⅲ oxidative stress Ⅲ blood pressure P eroxisome proliferator-activated receptor (PPAR)-␥ is a member of the nuclear receptor superfamily of ligand-activated transcription factors that plays an important role in the regulation of adipocyte differentiation and lipid and carbohydrate metabolism. 1,2 Its well-characterized increase in insulin sensitivity prompted the use of PPAR-␥ ligands of the thiazolidinedione (TZD) class, such as rosiglitazone, troglitazone, or pioglitazone, 3 for clinical treatment of type 2 diabetes mellitus. 4 Emerging evidence indicates that, in addition to its antihyperglycemic properties, TZD possesses beneficial effects in cardiovascular diseases, including hypertension, atherosclerosis, and heart failure. 1,5,6 With reference to hypertension, TZD decreases blood pressure in diabetic 7 and nondiabetic 8 hypertensive patients, and rosiglitazone reduces blood pressure and/or prevents the development of hypertension in animal models of insulin resistance and/or hypertension. 9 -11 Oxidative stress ...