Orphan nuclear receptor small heterodimer partner inhibits angiotensin II- stimulated PAI-1 expression in vascular smooth muscle cells.
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.
Lee
Kyeong-Min
KM
Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea.
Seo
Hye-Young
HY
Kim
Mi-Kyung
MK
Min
Ae-Kyung
AK
Ryu
Seong-Yeol
SY
Kim
Yoon-Nyun
YN
Park
Young Joo
YJ
Choi
Hueng-Sik
HS
Lee
Ki-Up
KU
Park
Wan-Ju
WJ
Park
Keun-Gyu
KG
Lee
In-Kyu
IK
D000256:Adenoviridae / Q000235:genetics; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D015152:Blotting, Northern; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051900:Smad3 Protein / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D017395:Plasminogen Activator Inhibitor 1; D018160:Receptors, Cytoplasmic and Nuclear; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C099713:nuclear receptor subfamily 0, group B, member 2; D000804:Angiotensin II