G(alpha)12/13 induction of CYR61 in association with arteriosclerotic intimal hyperplasia: effect of sphingosine-1-phosphate

Arterioscler Thromb Vasc Biol. 2011 Apr;31(4):861-9. doi: 10.1161/ATVBAHA.110.218552. Epub 2011 Jan 6.

Abstract

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 Gα(12) or Gα(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 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.

Conclusions: Gα(12/13) regulate AP-1-dependent CYR61 induction in VSMCs and promote VSMC migration, and they are upregulated with CYR61 in arteriosclerotic lesions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Arteriosclerosis / genetics
  • Arteriosclerosis / metabolism*
  • Arteriosclerosis / pathology
  • Cell Movement
  • Cysteine-Rich Protein 61 / genetics
  • Cysteine-Rich Protein 61 / metabolism*
  • Disease Models, Animal
  • Enzyme Activation
  • Female
  • GTP-Binding Protein alpha Subunits, G12-G13 / deficiency
  • GTP-Binding Protein alpha Subunits, G12-G13 / genetics
  • GTP-Binding Protein alpha Subunits, G12-G13 / metabolism*
  • HEK293 Cells
  • Humans
  • Hyperplasia
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Lysophospholipids / metabolism*
  • Male
  • Mice
  • Mice, Inbred ICR
  • Mice, Knockout
  • Middle Aged
  • Muscle, Smooth, Vascular / metabolism*
  • Muscle, Smooth, Vascular / pathology
  • Mutation
  • NADPH Oxidases / metabolism
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-jun / metabolism
  • RNA Interference
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism
  • Signal Transduction*
  • Sphingosine / analogs & derivatives*
  • Sphingosine / metabolism
  • Transcription Factor AP-1 / metabolism
  • Transfection
  • Tunica Intima / metabolism*
  • Tunica Intima / pathology
  • Up-Regulation

Substances

  • CCN1 protein, human
  • CCN1 protein, mouse
  • CCN1 protein, rat
  • Cysteine-Rich Protein 61
  • Lysophospholipids
  • Proto-Oncogene Proteins c-jun
  • Reactive Oxygen Species
  • Transcription Factor AP-1
  • sphingosine 1-phosphate
  • NADPH Oxidases
  • JNK Mitogen-Activated Protein Kinases
  • GTP-Binding Protein alpha Subunits, G12-G13
  • Sphingosine