Peroxisome proliferator–activated receptor-γ (PPARγ) ligands attenuate angiotensin II (Ang II)–induced atherosclerosis through interactions with vascular smooth muscle cell (VSMC)–specific PPARγ in hypercholesterolemic mice. Therefore, the purpose of this study was to determine the mechanism of Ang II–mediated intracellular regulation of PPARγ in VSMCs.

Incubation of cultured mouse aortic VSMCs with Ang II for 24 hours reduced abundance of PPARγ protein, mRNA, and transcriptional activity (P<0.001). This effect was attenuated by an angiotensin type 1 receptor antagonist, losartan. Ang II–induced PPARγ reduction was dependent on stimulation of transforming growth factor (TGF)-β1 as demonstrated using either a neutralizing antibody or small interfering RNA (siRNA). Ang II–induced TGF-β1 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-β1–induced PPARγ reduction. Blockade of TGF-β1 decreased p38 phosphorylation induced by Ang II. siRNA–mediated inhibition of histone deacetylase 3 attenuated p38-mediated reductions in PPARγ abundance.

These findings suggest that Ang II decreases PPARγ abundance in cultured VSMCs via an angiotensin type 1 receptor–dependent secretion of TGF-β1 via phosphorylation of p38 mitogen-activated protein kinase and histone deacetylase 3.