한빛사 논문
Young-June Jin1,*, Ramesh Chennupati1, Rui Li1, Guozheng Liang1, ShengPeng Wang1,2, András Iring1,3, Johannes Graumann4, Nina Wettschureck1,5,6,7 and Stefan Offermanns1,5,6,7,*
1Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany. 2Cardiovascular Research Center, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Yanta District, Xi’an, China. 3Laboratory of Molecular Medicine, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary. 4Scientific Service Group Biomolecular Mass Spectrometry, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany. 5Centre for Molecular Medicine, Medical Faculty, JW Goethe University Frankfurt, Frankfurt, Germany. 6Cardiopulmonary Institute (CPI), Frankfurt, Germany. 7German Center for Cardiovascular Research (DZHK), Rhine-Main Site, Frankfurt and Bad Nauheim, Germany
*Address correspondence to: Young-June Jin or Stefan Offermanns, Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim, Germany.
Abstract
Formation of NO by endothelial NOS (eNOS) is a central process in the homeostatic regulation of vascular functions including blood pressure regulation, and fluid shear stress exerted by the flowing blood is a main stimulus of eNOS activity. Previous work has identified several mechanosensing and -transducing processes in endothelial cells, which mediate this process and induce the stimulation of eNOS activity through phosphorylation of the enzyme via various kinases including AKT. How the initial mechanosensing and signaling processes are linked to eNOS phosphorylation is unclear. In human endothelial cells, we demonstrated that protein kinase N2 (PKN2), which is activated by flow through the mechanosensitive cation channel Piezo1 and Gq/G11-mediated signaling, as well as by Ca2+ and phosphoinositide-dependent protein kinase 1 (PDK1), plays a pivotal role in this process. Active PKN2 promoted the phosphorylation of human eNOS at serine 1177 and at a newly identified site, serine 1179. These phosphorylation events additively led to increased eNOS activity. PKN2-mediated eNOS phosphorylation at serine 1177 involved the phosphorylation of AKT synergistically with mTORC2-mediated AKT phosphorylation, whereas active PKN2 directly phosphorylated human eNOS at serine 1179. Mice with induced endothelium-specific deficiency of PKN2 showed strongly reduced flow-induced vasodilation and developed arterial hypertension accompanied by reduced eNOS activation. These results uncover a central mechanism that couples upstream mechanosignaling processes in endothelial cells to the regulation of eNOS-mediated NO formation, vascular tone, and blood pressure.
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