Published online before print June 23, 2005, doi: 10.1161/01.ATV.0000175295.09607.18
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© 2005 American Heart Association, Inc.
Vascular Biology |
Caveolin-1 Is Essential for Activation of Rac1 and NAD(P)H Oxidase After Angiotensin II Type 1 Receptor Stimulation in Vascular Smooth Muscle Cells
Role in Redox Signaling and Vascular Hypertrophy
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, Room 319, Atlanta, GA 30322. E-mail mfukai{at}emory.edu
Objective— Angiotensin II (Ang II) is a potent mediator of vascular hypertrophy in vascular smooth muscle cells (VSMCs). These effects are mediated through the Ang II type 1 receptor (AT1R) and require its trafficking through caveolin-1 (Cav1)–enriched lipid rafts and reactive oxygen species (ROS) derived from Rac1-dependent NAD(P)H oxidase. The specific role(s) of Cav1 in AT1R signaling is incompletely understood.
Methods and Results— Knockdown of Cav1 protein by small interfering RNA (siRNA) inhibits Ang II–stimulated Rac1 activation and membrane translocation, H2O2 production, ROS-dependent epidermal growth factor receptor (EGF-R) transactivation, and subsequent phosphorylation of Akt without affecting ROS-independent extracellular signal-regulated kinase 1/2 phosphorylation. Ang II stimulates tyrosine phosphorylation of Sos-1, a Rac–guanine nucleotide exchange factor, which is inhibited by Cav1 siRNA, demonstrating involvement of Cav1 in Rac1 activation. Detergent-free fractionation showed that EGF-Rs are found basally in Cav1-enriched lipid raft membranes and associate with Cav1. Ang II stimulates AT1R movement into these microdomains contemporaneously with the egress of EGF-R. Both aspects of this bidirectional receptor trafficking are inhibited by Cav1 siRNA. Moreover, Cav1 siRNA inhibits Ang II–induced vascular hypertrophy.
Conclusions— Cav1 plays an essential role in AT1R targeting into Cav1-enriched lipid rafts and Rac1 activation, which are required for proper organization of ROS-dependent Ang II signaling linked to VSMC hypertrophy.
Angiotensin II (Ang II)–induced vascular hypertrophy is dependent on caveolae/lipid rafts and reactive oxygen species (ROS) derived from NAD(P)H oxidase. Using caveolin-1 siRNA, we demonstrate that caveolin-1 plays an essential role in AT1 receptor targeting into caveolae/lipid rafts and Rac1 activation, which are required for ROS-dependent, growth-related Ang II signaling.
Key Words: angiotensin II • reactive oxygen species • caveolin • caveolae • vascular hypertrophy • vascular smooth muscle
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