Gα12/13 Induction of CYR61 in Association With Arteriosclerotic Intimal Hyperplasia
Effect of Sphingosine-1-Phosphate

Abstract
Objective—Gα12/13 play a role in oncogenic transformation and tumor growth. Cysteine-rich protein 61 (CYR61) is a growth-factor-inducible angiogenic factor. In view of potential overlapping functions between Gα12/13 and CYR61,this study investigated the role of these G proteins in CYR61 induction in association with hyperplastic vascular abnormality.
Methods and Results—Overexpression of activated Gα12 or Gα13 induced CYR61 expression in vascular smooth muscle cells (VSMCs). Gene knockdown and knockout experiments revealed that sphingosine-1-phosphate (S1P) treatment induced CYR61 via Gα12/13. JunD/activator protein-1 (AP-1) was identified as a transcription factor required for CYR61 transactivation by S1P. Deficiencies in Gα12/13 abrogated AP-1 activation and AP-1-mediated CYR61 induction. c-Jun N-terminal kinase was responsible for CYR61 induction. Moreover, deficiencies of Gα12/13 abolished c-Jun N-terminal kinase–dependent CYR61 induction by S1P. N-acetyl-l-cysteine or NADPH oxidase inhibitor treatment reversed CYR61 induction by S1P, indicating that reactive oxygen species are responsible for this process. The levels of Gα12/13 were increased within thickened intimas and medias in wire-injured mouse femoral arteries, which was accompanied by simultaneous CYR61 induction. Moreover, Gα12/13 and CYR61 were costained in the arteriosclerotic lesions immediately adjacent to human tumor tissues.
Conclusion—Gα12/13 regulate AP-1-dependent CYR61 induction in VSMCs and promote VSMC migration, and they are upregulated with CYR61 in arteriosclerotic lesions.
- atherosclerosis
- G proteins
- oncogenes
- signal transduction
- vascular biology
- Gα12/13
- cysteine-rich protein 61
- sphingosine-1-phosphate
- vascular smooth muscle cell
- Received June 24, 2010.
- Accepted December 23, 2010.
- © 2011 American Heart Association, Inc.
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- Gα12/13 Induction of CYR61 in Association With Arteriosclerotic Intimal HyperplasiaYoung Mi Kim, Sung-Chul Lim, Chang Yeob Han, Hee Yeon Kay, Il Je Cho, Sung Hwan Ki, Moo Yeol Lee, Hyuck Moon Kwon, Chang Ho Lee and Sang Geon KimArteriosclerosis, Thrombosis, and Vascular Biology. 2011;ATVBAHA.110.218552, originally published January 6, 2011https://doi.org/10.1161/ATVBAHA.110.218552
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- Gα12/13 Induction of CYR61 in Association With Arteriosclerotic Intimal HyperplasiaYoung Mi Kim, Sung-Chul Lim, Chang Yeob Han, Hee Yeon Kay, Il Je Cho, Sung Hwan Ki, Moo Yeol Lee, Hyuck Moon Kwon, Chang Ho Lee and Sang Geon KimArteriosclerosis, Thrombosis, and Vascular Biology. 2011;ATVBAHA.110.218552, originally published January 6, 2011https://doi.org/10.1161/ATVBAHA.110.218552