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dc.contributor.authorReventun, Paula
dc.contributor.authorAlique, Matilde
dc.contributor.authorCuadrado, Irene
dc.contributor.authorMárquez, Susana
dc.contributor.authorToro, Rocío
dc.contributor.authorZaragoza Sánchez, Carlos 
dc.contributor.authorSaura, Marta
dc.description.abstractOBJECTIVE: ILK (integrin-linked kinase) plays a key role in controlling vasomotor tone and is decreased in atherosclerosis. The objective of this study is to test whether nitric oxide (NO) regulates ILK in vascular remodeling. APPROACH AND RESULTS: We found a striking correlation between increased levels of inducible nitric oxide and decreased ILK levels in human atherosclerosis and in a mouse model of vascular remodeling (carotid artery ligation) comparing with inducible NO synthase knockout mice. Inducible NO synthase induction produced the same result in mouse aortic endothelial cells, and these effects were mimicked by an NO donor in a time-dependent manner. We found that NO decreased ILK protein stability by promoting the dissociation of the complex ILK/heat shock protein 90/endothelial NO synthase, leading to endothelial NO synthase uncoupling. NO also destabilized ILK signaling platform and lead to decreased levels of paxillin and α-parvin. ILK phosphorylation of its downstream target GSK3-β was decreased by NO. Mechanistically, NO increased ILK ubiquitination mediated by the E3 ubiquitin ligase CHIP, but ILK ubiquitination was not followed by proteasome degradation. Alternatively, NO drove ILK to degradation through the endocytic-lysosomal pathway. ILK colocalized with the lysosome marker LAMP-1 in endothelial cells, and inhibition of lysosome activity with chloroquine reversed the effect of NO. Likewise, ILK colocalized with the early endosome marker EEA1. ILK endocytosis proceeded via dynamin because a specific inhibitor of dynamin (Dyngo 4a) was able to reverse ILK endocytosis and its lysosome degradation. CONCLUSIONS: Endocytosis regulates ILK signaling in vascular remodeling where there is an overload of inducible NO, and thus its inhibition may represent a novel target to fight atherosclerotic disease.eng
dc.publisherArteriosclerosis, Thrombosis, and Vascular
dc.rightsAtribución-NoComercial-SinDerivadas 3.0 España*
dc.subjectNitric oxidespa
dc.subjectNitric oxide synthasespa
dc.titleiNOS-Derived Nitric Oxide Induces Integrin-Linked Kinase Endocytic Lysosome-Mediated Degradation in the Vascular Endothelium.eng
dc.description.extent23834 KBspa

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