iNOS-Derived Nitric Oxide Induces Integrin-Linked Kinase Endocytic Lysosome-Mediated Degradation in the Vascular Endothelium

• DOI: 10.1161/atvbaha.117.309560
• Publication Date: 2017-05-26T00:55:21Z
• Authors: Paula Reventun; Matilde Alique; Irene Cuadrado; Susana Márquez; Rocío Toro; Carlos Zaragoza; Marta Saura
• Keywords: Integrin-linked kinase

ILK (integrin-linked kinase) plays a key role in controlling vasomotor tone and is decreased atherosclerosis. The objective of this study to test whether nitric oxide (NO) regulates vascular remodeling.We found striking correlation between increased levels inducible human atherosclerosis mouse model remodeling (carotid artery ligation) comparing with iNOS (inducible NO synthase) knockout mice. induction produced the same result aortic endothelial cells, these effects were mimicked by an donor time-dependent manner. We that protein stability promoting dissociation complex ILK/Hsp90 (heat shock 90)/eNOS (endothelial synthase), leading eNOS uncoupling. also destabilized signaling platform lead paxillin α-parvin. phosphorylation its downstream target GSK3-β (glycogen synthase kinase 3 beta) was NO. Mechanistically, ubiquitination mediated E3 ubiquitin ligase CHIP (C terminus HSC70-interacting protein), but not followed proteasome degradation. Alternatively, drove degradation through endocytic-lysosomal pathway. colocalized lysosome marker LAMP-1 (lysosomal-associated membrane 1) inhibition activity chloroquine reversed effect Likewise, early endosome EEA1 (early antigen 1). endocytosis proceeded via dynamin because specific inhibitor (Dyngo 4a) able reverse degradation.Endocytosis where there overload NO, thus may represent novel fight atherosclerotic disease.