Regulation of Peroxisome Proliferator-Activated Receptor-γ by Angiotensin II Via Transforming Growth Factor-β1-Activated p38 Mitogen-Activated Protein Kinase in Aortic Smooth Muscle Cells

Objective-Peroxisome proliferator-activated receptor-gamma (PPAR gamma) ligands attenuate angiotensin II (Ang II)-induced atherosclerosis through interactions with vascular smooth muscle cell (VSMC)-specific PPAR gamma in hypercholesterolemic mice. Therefore, the purpose of this study was to determine the mechanism of Ang II-mediated intracellular regulation of PPAR gamma in VSMCs. Methods and Results-Incubation of cultured mouse aortic VSMCs with Ang II for 24 hours reduced abundance of PPAR gamma protein, mRNA, and transcriptional activity (P < 0.001). This effect was attenuated by an angiotensin type 1 receptor antagonist, losartan. Ang II-induced PPAR gamma reduction was dependent on stimulation of transforming growth factor (TGF)-beta 1 as demonstrated using either a neutralizing antibody or small interfering RNA (siRNA). Ang II-induced TGF-beta 1 secretion was dependent on epidermal growth factor receptor kinase activation through reactive oxygen species production. Inhibition of p38 mitogen-activated protein kinase by SB203580 or siRNA inhibited both Ang II- and TGF-beta 1-induced PPAR gamma reduction. Blockade of TGF-beta 1 decreased p38 phosphorylation induced by Ang II. siRNA-mediated inhibition of histone deacetylase 3 attenuated p38-mediated reductions in PPAR gamma abundance. Conclusion-These findings suggest that Ang II decreases PPAR gamma abundance in cultured VSMCs via an angiotensin type 1 receptor-dependent secretion of TGF-beta 1 via phosphorylation of p38 mitogen-activated protein kinase and histone deacetylase 3. (Arterioscler Thromb Vasc Biol. 2012; 32:397-405.)