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
Subramanian, Venkateswaran, Golledge, Jonathan, Heywood, Elizabeth B., Bruemmer, Dennis, and Daugherty , Alan (2012) 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. Arteriosclerosis, Thrombosis and Vascular Biology, 32. pp. 397-405.
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OBJECTIVE: 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.
METHODS AND RESULTS: 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.
CONCLUSIONS: 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.
|Item Type:||Article (Refereed Research - C1)|
|Keywords:||angiotensin II; atherosclerosis; signal transduction; vascular biology; smooth muscle cells|
|Date Deposited:||27 Mar 2012 02:24|
|FoR Codes:||11 MEDICAL AND HEALTH SCIENCES > 1101 Medical Biochemistry and Metabolomics > 110103 Medical Biochemistry: Inorganic Elements and Compounds @ 100%|
|SEO Codes:||92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920103 Cardiovascular System and Diseases @ 100%|
|Citation Count from Web of Science||