Abstract
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 βPIX, 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/βPIX/Rac-1 signaling, thus generating oxidative vascular dysfunction.
| Original language | English |
|---|---|
| Pages (from-to) | 1028-1034 |
| Number of pages | 7 |
| Journal | Hypertension |
| Volume | 54 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - Nov 2009 |
Fingerprint
Keywords
- Endothelial dysfunction
- High pressure
- Integrin signaling
- Mechanotransduction
- Oxidative stress
ASJC Scopus subject areas
- Internal Medicine
Cite this
Pressure-induced vascular oxidative stress is mediated through activation of integrin-linked kinase 1/βPIX/Rac-1 pathway. / Vecchione, Carmine; Carnevale, Daniela; Di Pardo, Alba; Gentile, Maria Teresa; Damato, Antonio; Cocozza, Germana; Antenucci, Giovanna; Mascio, Giada; Bettarini, Umberto; Landolfi, Alessandro; Iorio, Luca; Maffei, Angelo; Lembo, Giuseppe.
In: Hypertension, Vol. 54, No. 5, 11.2009, p. 1028-1034.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Pressure-induced vascular oxidative stress is mediated through activation of integrin-linked kinase 1/βPIX/Rac-1 pathway
AU - Vecchione, Carmine
AU - Carnevale, Daniela
AU - Di Pardo, Alba
AU - Gentile, Maria Teresa
AU - Damato, Antonio
AU - Cocozza, Germana
AU - Antenucci, Giovanna
AU - Mascio, Giada
AU - Bettarini, Umberto
AU - Landolfi, Alessandro
AU - Iorio, Luca
AU - Maffei, Angelo
AU - Lembo, Giuseppe
PY - 2009/11
Y1 - 2009/11
N2 - 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 βPIX, 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/βPIX/Rac-1 signaling, thus generating oxidative vascular dysfunction.
AB - 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 βPIX, 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/βPIX/Rac-1 signaling, thus generating oxidative vascular dysfunction.
KW - Endothelial dysfunction
KW - High pressure
KW - Integrin signaling
KW - Mechanotransduction
KW - Oxidative stress
UR - http://www.scopus.com/inward/record.url?scp=70449725149&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=70449725149&partnerID=8YFLogxK
U2 - 10.1161/HYPERTENSIONAHA.109.136572
DO - 10.1161/HYPERTENSIONAHA.109.136572
M3 - Article
C2 - 19770407
AN - SCOPUS:70449725149
VL - 54
SP - 1028
EP - 1034
JO - Hypertension
JF - Hypertension
SN - 0194-911X
IS - 5
ER -