Pressure-induced vascular oxidative stress is mediated through activation of integrin-linked kinase 1/betaPIX/Rac-1 pathway.
High blood pressure induces a mechanical stress on vascular walls and evokes oxidative stress and vascular dysfunction. The aim of this study was to characterize the intracellular signaling causing vascular oxidative stress in response to pressure. In carotid arteries subjected to high pressure levels, we observed not only an impaired vasorelaxation, increased superoxide production, and NADPH oxidase activity, but also a concomitant activation of Rac-1, a small G protein. Selective inhibition of Rac-1, with an adenovirus carrying a dominant-negative Rac-1 mutant, significantly reduced NADPH oxidase activity and oxidative stress and, more importantly, rescued vascular function in carotid arteries at high pressure. The analysis of molecular events associated with mechanotransduction demonstrated at high pressure levels an overexpression of integrin-linked kinase 1 and its recruitment to plasma membrane interacting with paxillin. The inhibition of integrin-linked kinase 1 by small interfering RNA impaired Rac-1 activation and rescued oxidative stress-induced vascular dysfunction in response to high pressure. Finally, we showed that betaPIX, a guanine-nucleotide exchange factor, is the intermediate molecule recruited by integrin-linked kinase 1, converging the intracellular signaling toward Rac-1-mediated oxidative vascular dysfunction during pressure overload. Our data demonstrate that biomechanical stress evoked by high blood pressure triggers an integrin-linked kinase 1/betaPIX/Rac-1 signaling, thus generating oxidative vascular dysfunction.
Vecchione
Carmine
C
Department of Angio-Cardio-Neurology, Neuromed Institute Istituto Di Ricovero e Cura a Carattere Scientifico, Pozzilli, Italy.
Carnevale
Daniela
D
Di Pardo
Alba
A
Gentile
Maria Teresa
MT
Damato
Antonio
A
Cocozza
Germana
G
Antenucci
Giovanna
G
Mascio
Giada
G
Bettarini
Umberto
U
Landolfi
Alessandro
A
Iorio
Luca
L
Maffei
Angelo
A
Lembo
Giuseppe
G
D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000502:physiology; D006801:Humans; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D051419:Paxillin / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000187:drug effects; D013314:Stress, Mechanical; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D000099200:Scaffold Protein ILK
D051419:Paxillin; D017346:Protein Serine-Threonine Kinases; D020830:rac1 GTP-Binding Protein; D000099200:Scaffold Protein ILK