Orphan nuclear receptor small heterodimer partner inhibits angiotensin II-stimulated PAI-1 expression in vascular smooth muscle cells.
10.3858/emm.2010.42.1.002
- Author:
Kyeong Min LEE
1
;
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
Author Information
1. Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu 700-721, Korea. leei@knu.ac.kr
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
angiotensin II;
atherosclerosis;
muscle, smooth, vascular;
nuclear receptor subfamily 0, group B, member 2;
plasminogen activator inhibitor 1;
transforming growth factor beta
- MeSH:
Adenoviridae/genetics;
Angiotensin II/*pharmacology;
Animals;
Blotting, Northern;
Cells, Cultured;
Electrophoretic Mobility Shift Assay;
Genetic Vectors/genetics;
Humans;
Mice;
Muscle, Smooth, Vascular/*cytology;
Myocytes, Smooth Muscle/*drug effects/*metabolism;
Plasminogen Activator Inhibitor 1/*genetics;
Promoter Regions, Genetic/genetics;
Rats;
Receptors, Cytoplasmic and Nuclear/genetics/*metabolism;
Reverse Transcriptase Polymerase Chain Reaction;
Smad3 Protein/genetics;
Transforming Growth Factor beta/pharmacology
- From:Experimental & Molecular Medicine
2010;42(1):21-29
- CountryRepublic of Korea
- Language:English
-
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.
