Orphan Nuclear Receptor Small Heterodimer Partner Inhibits Angiotensin II- Stimulated PAI-1 Expression in Vascular Smooth Muscle Cells

Overview

Journal Exp Mol Med

Specialties Biochemistry
Molecular Biology

Date 2009 Nov 6

PMID 19887897

Citations 3

Authors

Kyeong-Min Lee

Hye-Young Seo

Mi-Kyung Kim

Ae-Kyung Min

Seong-Yeol Ryu

Yoon-Nyun Kim

Young Joo Park

Hueng-Sik Choi

Ki-Up Lee

Wan-Ju Park

Keun-Gyu Park

In-Kyu Lee

Affiliations

Soon will be listed here.

Abstract

Angiotensin II is a major effector molecule in the development of cardiovascular disease. In vascular smooth muscle cells (VSMCs), angiotensin II promotes cellular proliferation and extracellular matrix accumulation through the upregulation of plasminogen activator inhibitor-1 (PAI-1) expression. Previously, we demonstrated that small heterodimer partner (SHP) represses PAI-1 expression in the liver through the inhibition of TGF-beta signaling pathways. Here, we investigated whether SHP inhibited angiotensin II-stimulated PAI-1 expression in VSMCs. Adenovirus-mediated overexpression of SHP (Ad- SHP) in VSMCs inhibited angiotensin II- and TGF-beta-stimulated PAI-1 expression. Ad-SHP also inhibited angiotensin II-, TGF-beta- and Smad3-stimulated PAI-1 promoter activity, and angiotensin II-stimulated AP-1 activity. The level of PAI-1 expression was significantly higher in VSMCs of SHP(-/-) mice than wild type mice. Moreover, loss of SHP increased PAI-1 mRNA expression after angiotensin II treatment. These results suggest that SHP inhibits PAI-1 expression in VSMCs through the suppression of TGF-beta/Smad3 and AP-1 activity. Thus, agents that target the induction of SHP expression in VSMCs might help prevent the development and progression of atherosclerosis.

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