G alpha(12/13) Induction of CYR61 in Association With Arteriosclerotic Intimal Hyperplasia Effect of Sphingosine-1-Phosphate

Abstract

Objective-G alpha(12/13) 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 G alpha(12/13) 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 G alpha(12) or G alpha(13) induced CYR61 expression in vascular smooth muscle cells (VSMCs). Gene knockdown and knockout experiments revealed that sphingosine-1-phosphate (S1P) treatment induced CYR61 via G alpha(12/13). JunD/activator protein-1 (AP-1) was identified as a transcription factor required for CYR61 transactivation by S1P. Deficiencies in G alpha(12/13) abrogated AP-1 activation and AP-1-mediated CYR61 induction. c-Jun N-terminal kinase was responsible for CYR61 induction. Moreover, deficiencies of G alpha(12/13) 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 G alpha(12/13) were increased within thickened intimas and medias in wire-injured mouse femoral arteries, which was accompanied by simultaneous CYR61 induction. Moreover, G alpha(12/13) and CYR61 were costained in the arteriosclerotic lesions immediately adjacent to human tumor tissues. Conclusion-G alpha(12/13) regulate AP-1-dependent CYR61 induction in VSMCs and promote VSMC migration, and they are upregulated with CYR61 in arteriosclerotic lesions. (Arterioscler Thromb Vasc Biol. 2011;31:861-869.)