cAbl tyrosine kinase mediates reactive oxygen species- and caveolin-dependent AT1 receptor signaling in vascular smooth muscle: Role in vascular hypertrophy

Masuko Ushio-Fukai, Lian Zuo, Satoshi Ikeda, Taiki Tojo, Nikolay A. Patrushev, R. Wayne Alexander

Research output: Contribution to journalArticle

70 Scopus citations

Abstract

Important output signals of the angiotensin subtype 1 receptor (AT 1R) in vascular smooth muscle cells (VSMCs) are mediated by angiotensin II (Ang II)-stimulated transactivation of the epidermal growth factor receptor (EGF-R), which is critical for vascular hypertrophy. Ang II-induced EGF-R transactivation is mediated through cSrc, a proximal target of reactive oxygen species (ROS) derived from NAD(P)H oxidase (NOX) and is dependent on AT1R trafficking through caveolin1 (Cav1)-enriched lipid rafts. Underlying molecular mechanisms are incompletely understood. The nonreceptor tyrosine kinase, proto-oncogene cAb1 is a substrate of Src and is a major mediator for ROS-dependent tyrosine phosphorylation of Cav1. We thus hypothesized that cAb1 is important for ROS-, cSrc-, and Cav1-dependent growth-related AT1R signal transduction. Here we show that Ang II induces tyrosine phosphorylation of cAbl in rat VSMCs and mouse aorta, and that Ang II promotes association of cAbl with AT1R, both of which are Src-dependent. Pretreatment of rat VSMCs with the NOX inhibitor diphenylene iodonium or the antioxidants N-acetylcysteine or ebselen significantly inhibited Ang II-induced cAbl phosphorylation. Cell fractionation shows that both EGF-Rs and cAbl are found basally in Cav1-enriched membrane fractions. Knockdown of cAbl protein using small interference RNA inhibits Ang II-stimulated: (1) trafficking of AT1R into, and EGF-R out of, Cav1-enriched lipid rafts; (2) EGF-R transactivation; (3) appearance of the transactivated EGF-R and phospho-Cav1 at focal adhesions; and (4) vascular hypertrophy. These studies provide a novel role of cAbl in the spatial and temporal organization of growth-related AT1R signaling in VSMCs and suggest that cAbl may be generally important in signaling of G-protein coupled receptors.

Original languageEnglish (US)
Pages (from-to)829-836
Number of pages8
JournalCirculation research
Volume97
Issue number8
DOIs
Publication statusPublished - Oct 14 2005
Externally publishedYes

    Fingerprint

Keywords

  • Angiotensin II
  • Caveolin-1
  • NAD(P)H oxidase
  • Vascular smooth muscle
  • cAbl

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this