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(Circulation Research. 2005;97:829.)
© 2005 American Heart Association, Inc.

Molecular Medicine

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

From the Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Ga.

Correspondence to Masuko Ushio-Fukai, PhD, Division of Cardiology, Emory University School of Medicine, 1639 Pierce Dr, Rm 319, Atlanta, GA 30322. E-mail mfukai{at}emory.edu

Important output signals of the angiotensin subtype 1 receptor (AT₁R) 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 cAbl is a substrate of Src and is a major mediator for ROS-dependent tyrosine phosphorylation of Cav1. We thus hypothesized that cAbl 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.

Key Words: cAbl • caveolin-1 • NAD(P)H oxidase • angiotensin II • vascular smooth muscle

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