Exp Mol Med.
2010 Jan;42(1):21-29. 10.3858/emm.2010.42.1.002.
Orphan nuclear receptor small heterodimer partner inhibits angiotensin II-stimulated PAI-1 expression in vascular smooth muscle cells
- Affiliations
-
- 1Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu 700-721, Korea. leei@knu.ac.kr
- 2Department of Internal Medicine and Institute for Medical Science, Keimyung University School of Medicine, Daegu 700-712, Korea. kgpark@dsmc.or.kr
- 3Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-744, Korea.
- 4Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Korea.
- 5Department of Internal Medicine, University of Ulsan College of Medicine, Seoul 138-736, Korea.
- 6College of Nursing and Research, Institute of Nursing Science, Kyungpook National University, Daegu 700-721, Korea.
- 7WCU project "Development for new drug-target in complication of metabolic syndrome", Kyungpook National University School of Medicine, Daegu 700-721, Korea.
- KMID: 946666
- DOI: http://doi.org/10.3858/emm.2010.42.1.002
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.
Keyword
MeSH Terms
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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
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