Published online before print June 23, 2005, doi: 10.1161/01.ATV.0000175295.09607.18
© 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
This article has been cited by other articles:
 |
|
 |
|
  F. D. Oakley, R. L. Smith, and J. F. Engelhardt Lipid Rafts and Caveolin-1 Coordinate Interleukin-1{beta} (IL-1{beta})-dependent Activation of NF{kappa}B by Controlling Endocytosis of Nox2 and IL-1{beta} Receptor 1 from the Plasma Membrane J. Biol. Chem., November 27, 2009; 284(48): 33255 - 33264. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Senou, M. J. Costa, C. Massart, M. Thimmesch, C. Khalifa, S. Poncin, M. Boucquey, A.-C. Gerard, J.-N. Audinot, C. Dessy, et al. Role of caveolin-1 in thyroid phenotype, cell homeostasis, and hormone synthesis: in vivo study of caveolin-1 knockout mice Am J Physiol Endocrinol Metab, August 1, 2009; 297(2): E438 - E451. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. H. Pojoga, T. M. Yao, S. Sinha, R. L. Ross, J. C. Lin, J. D. Raffetto, G. K. Adler, G. H. Williams, and R. A. Khalil Effect of dietary sodium on vasoconstriction and eNOS-mediated vascular relaxation in caveolin-1-deficient mice Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1258 - H1265. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Hu, R. D. Ye, M. C. Dinauer, A. B. Malik, and R. D. Minshall Neutrophil caveolin-1 expression contributes to mechanism of lung inflammation and injury Am J Physiol Lung Cell Mol Physiol, February 1, 2008; 294(2): L178 - L186. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Zemans and G. P. Downey Role of caveolin-1 in regulation of inflammation: different strokes for different folks Am J Physiol Lung Cell Mol Physiol, February 1, 2008; 294(2): L175 - L177. [Full Text] [PDF]
|
|
|
|
 |
|
 A. E. Linder, K. M. Thakali, J. M. Thompson, S. W. Watts, R. C. Webb, and R. Leite Methyl-beta-cyclodextrin Prevents Angiotensin II-Induced Tachyphylactic Contractile Responses in Rat Aorta J. Pharmacol. Exp. Ther., October 1, 2007; 323(1): 78 - 84. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Sachse and G. Wolf Angiotensin II Induced Reactive Oxygen Species and the Kidney J. Am. Soc. Nephrol., September 1, 2007; 18(9): 2439 - 2446. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Carlile-Klusacek and V. Rizzo Endothelial cytoskeletal reorganization in response to PAR1 stimulation is mediated by membrane rafts but not caveolae Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H366 - H375. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. K. Mehta and K. K. Griendling Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system Am J Physiol Cell Physiol, January 1, 2007; 292(1): C82 - C97. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Hunter and G. F. Nixon Spatial Compartmentalization of Tumor Necrosis Factor (TNF) Receptor 1-dependent Signaling Pathways in Human Airway Smooth Muscle Cells: LIPID RAFTS ARE ESSENTIAL FOR TNF-{alpha}-MEDIATED ACTIVATION OF RhoA BUT DISPENSABLE FOR THE ACTIVATION OF THE NF-{kappa}B AND MAPK PATHWAYS J. Biol. Chem., November 10, 2006; 281(45): 34705 - 34715. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Ushio-Fukai and R. W. Alexander Caveolin-Dependent Angiotensin II Type 1 Receptor Signaling in Vascular Smooth Muscle Hypertension, November 1, 2006; 48(5): 797 - 803. [Full Text] [PDF]
|
|
|
|
|
|
H. Ohtsu, H. Suzuki, H. Nakashima, S. Dhobale, G. D. Frank, E. D. Motley, and S. Eguchi Angiotensin II Signal Transduction Through Small GTP-Binding Proteins: Mechanism and Significance in Vascular Smooth Muscle Cells Hypertension, October 1, 2006; 48(4): 534 - 540. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Ushio-Fukai Localizing NADPH Oxidase-Derived ROS Sci. Signal., August 22, 2006; 2006(349): re8 - re8. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. N. Lyle and K. K. Griendling Modulation of vascular smooth muscle signaling by reactive oxygen species. Physiology, August 1, 2006; 21: 269 - 280. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. E. Clempus and K. K. Griendling Reactive oxygen species signaling in vascular smooth muscle cells Cardiovasc Res, July 15, 2006; 71(2): 216 - 225. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Ohtsu, P. J. Dempsey, and S. Eguchi ADAMs as mediators of EGF receptor transactivation by G protein-coupled receptors Am J Physiol Cell Physiol, July 1, 2006; 291(1): C1 - C10. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Satoh, H. Ogita, K. Takeshita, Y. Mukai, D. J. Kwiatkowski, and J. K. Liao Requirement of Rac1 in the development of cardiac hypertrophy PNAS, May 9, 2006; 103(19): 7432 - 7437. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Hunyady and K. J. Catt Pleiotropic AT1 Receptor Signaling Pathways Mediating Physiological and Pathogenic Actions of Angiotensin II Mol. Endocrinol., May 1, 2006; 20(5): 953 - 970. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. Brown, D. P. Del Re, and M. A. Sussman The Rac and Rho Hall of Fame: A Decade of Hypertrophic Signaling Hits Circ. Res., March 31, 2006; 98(6): 730 - 742. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. L. Hordijk Regulation of NADPH Oxidases: The Role of Rac Proteins Circ. Res., March 3, 2006; 98(4): 453 - 462. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. D. Hardin and J. Vallejo Caveolins in vascular smooth muscle: Form organizing function Cardiovasc Res, March 1, 2006; 69(4): 808 - 815. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Touyz Lipid Rafts Take Center Stage in Endothelial Cell Redox Signaling by Death Receptors Hypertension, January 1, 2006; 47(1): 16 - 18. [Full Text] [PDF]
|
|
|
|
|
|
M. Ushio-Fukai, L. Zuo, S. Ikeda, T. Tojo, N. A. Patrushev, and R. W. Alexander cAbl Tyrosine Kinase Mediates Reactive Oxygen Species- and Caveolin-Dependent AT1 Receptor Signaling in Vascular Smooth Muscle: Role in Vascular Hypertrophy Circ. Res., October 14, 2005; 97(8): 829 - 836. [Abstract] [Full Text] [PDF]
|
|