title: Ca2+ -regulated lysosome fusion mediates angiotensin II-induced lipid raft clustering in mesenteric endothelial cells.
abstract: It has been reported that intracellular Ca2+ is involved in lysosome fusion and membrane repair in skeletal cells. Given that angiotensin II (Ang II) elicits an increase in intracellular Ca2+ and that lysosome fusion is a crucial mediator of lipid raft (LR) clustering, we hypothesized that Ang II induces lysosome fusion and activates LR formation in rat mesenteric endothelial cells (MECs). We found that Ang II acutely increased intracellular Ca2+ content, an effect that was inhibited by the extracellular Ca2+ chelator ethylene glycol tetraacetic acid (EGTA) and the inositol 1,4,5-trisphosphate (IP3)-induced Ca2+ release inhibitor 2-aminoethoxydiphenyl borate (2-APB). Further study showed that EGTA almost completely blocked Ang II-induced lysosome fusion, the translocation of acid sphingomyelinase (ASMase) to LR clusters, ASMase activation and NADPH (nicotinamide adenine dinucleotide phosphate) oxidase activation. In contrast, 2-APB had a slight inhibitory effect. Functionally, both the lysosome inhibitor bafilomycin A1 and the ASMase inhibitor amitriptyline reversed Ang II-induced impairment of vasodilation. We conclude that Ca2+ -regulated lysosome fusion mediates the Ang II-induced regulation of the LR-redox signaling pathway and mesenteric endothelial dysfunction.
authors.affiliation: State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension, Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Laboratory of Vascular Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.|Shanghai Institute of Hypertension, Shanghai, China.
authors.forename: Wei-Qing
authors.initials: WQ
authors.lastname: Han
authors.affiliation: State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension, Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Shanghai Institute of Hypertension, Shanghai, China.
authors.forename: Wen-Dong
authors.initials: WD
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension, Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Laboratory of Vascular Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension, Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Shanghai Institute of Hypertension, Shanghai, China.
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension, Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Shanghai Institute of Hypertension, Shanghai, China.
authors.forename: Yong-Jie
authors.initials: YJ
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension, Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Laboratory of Vascular Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.|Shanghai Institute of Hypertension, Shanghai, China.
authors.forename: Ping-Jin
authors.initials: PJ
authors.lastname: Gao
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001896:Boron Compounds / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D065096:Calcium Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism*; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism*; D008638:Mesenteric Arteries / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D001896:Boron Compounds; D065096:Calcium Chelating Agents; D000804:Angiotensin II; D004533:Egtazic Acid; C109986:2-aminoethoxydiphenyl borate; D002118:Calcium