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Regulation of peroxisome proliferator-activated receptor-? by angiotensin II via transforming growth factor-?1-activated p38 mitogen-activated protein kinase in aortic smooth muscle cells.

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

SUBMITTER: Subramanian V

PROVIDER: S-EPMC3262055 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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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 V Golledge Jonathan J Heywood Elizabeth B EB Bruemmer Dennis D Daugherty Alan A

Arteriosclerosis, thrombosis, and vascular biology 20111117 2

<h4>Objective</h4>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.<h4>Methods and results</h4>Incubation of cultured mouse aortic VSMCs with Ang II for 24 hours reduced abundance of PPARγ prote ...[more]

PMID: 22095985

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Project description:Peroxisome proliferator-activated receptor-? (PPAR?) plays an important role in the vasculature; however, the role of PPAR? in abdominal aortic aneurysms (AAA) is not well understood. We hypothesized that PPAR? in smooth muscle cells (SMCs) attenuates the development of AAA. We also investigated PPAR?-mediated signaling pathways that may prevent the development of AAA.We determined whether periaortic application of CaCl(2) renders vascular SMC-selective PPAR? knockout (SMPG KO) mice more susceptible to destruction of normal aortic wall architecture.There is evidence of increased vessel dilatation in the abdominal aorta 6 weeks after 0.25M periaortic CaCl(2) application in SMPG KO mice compared with littermate controls (1.4 ± 0.3 mm [n = 8] vs 1.1 ± 0.2 mm [n = 7]; P = .000119). Results from SMPG KO mice indicate medial layer elastin degradation was greater 6 weeks after abluminal application of CaCl(2) to the abdominal aorta (P < .01). Activated cathepsin S, a potent elastin-degrading enzyme, was increased in SMPG KO mice vs wild-type controls. To further identify a role of PPAR? signaling in reducing the development of AAA, we demonstrated that adenoviral-mediated PPAR? overexpression in cultured rat aortic SMCs decreases (P = .022) the messenger RNA levels of cathepsin S. In addition, a chromatin immunoprecipitation assay detected PPAR? bound to a peroxisome proliferator-activated receptor response element (PPRE) -141 to -159 bp upstream of the cathepsin S gene sequence in mouse aortic SMCs. Also, adenoviral-mediated PPAR? overexpression and knockdown in cultured rat aortic SMCs decreases (P = .013) and increases (P = .018) expression of activated cathepsin S. Finally, immunohistochemistry demonstrated a greater inflammatory infiltrate in SMPG KO mouse aortas, as evidenced by elevations in F4/80 and tumor necrosis factor-? expression.In this study, we identify PPAR? as an important contributor in attenuating the development of aortic aneurysms by demonstrating that loss of PPAR? in vascular SMCs promotes aortic dilatation and elastin degradation. Thus, PPAR? activation may be potentially promising medical therapy in reducing the risk of AAA progression and rupture.

Dataset Information

Regulation of peroxisome proliferator-activated receptor-? by angiotensin II via transforming growth factor-?1-activated p38 mitogen-activated protein kinase in aortic smooth muscle cells.

Publications

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.

Similar Datasets

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