Gα_12/13 Induction of CYR61 in Association With Arteriosclerotic Intimal Hyperplasia

Objective—Gα_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 Gα_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 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 Gα_12/13. JunD/activator protein-1 (AP-1) was identified as a transcription factor required for CYR61 transactivation by S1P. Deficiencies in Gα_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 Gα_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 Gα_12/13 were increased within thickened intimas and medias in wire-injured mouse femoral arteries, which was accompanied by simultaneous CYR61 induction. Moreover, Gα_12/13 and CYR61 were costained in the arteriosclerotic lesions immediately adjacent to human tumor tissues.

Conclusion—Gα_12/13 regulate AP-1-dependent CYR61 induction in VSMCs and promote VSMC migration, and they are upregulated with CYR61 in arteriosclerotic lesions.