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.
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.


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.
Zuo
Lian
L
Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Ushio-Fukai
Masuko
M
Ikeda
Satoshi
S
Hilenski
Lula
L
Patrushev
Nikolay
N
Alexander
R Wayne
RW
D008841:Actin Cytoskeleton / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000378:metabolism; D006984:Hypertrophy; D021962:Membrane Microdomains / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism*; D010084:Oxidation-Reduction; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D020837:SOS1 Protein / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D051242:Caveolin 1; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D020837:SOS1 Protein; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D014443:Tyrosine; D019255:NADPH Oxidases; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D020830:rac1 GTP-Binding Protein