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Coupling of Integrin α5 to Annexin A2 by Flow Drives Endothelial Activation.
Zhang, Chenghu; Zhou, Ting; Chen, Zhipeng; Yan, Meng; Li, Bochuan; Lv, Huizhen; Wang, Chunjiong; Xiang, Song; Shi, Lei; Zhu, Yi; Ai, Ding.
Afiliação
  • Zhang C; State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) and Department of Physiology and Pathophysiology, Tianjin Key Laboratory of Metabolic Diseases (C.Z., T.Z., Z.C., M.Y., B.L., H.L., C.W., Y.Z., D.A.), Tianjin Medical Univer
  • Zhou T; State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) and Department of Physiology and Pathophysiology, Tianjin Key Laboratory of Metabolic Diseases (C.Z., T.Z., Z.C., M.Y., B.L., H.L., C.W., Y.Z., D.A.), Tianjin Medical Univer
  • Chen Z; State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) and Department of Physiology and Pathophysiology, Tianjin Key Laboratory of Metabolic Diseases (C.Z., T.Z., Z.C., M.Y., B.L., H.L., C.W., Y.Z., D.A.), Tianjin Medical Univer
  • Yan M; State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) and Department of Physiology and Pathophysiology, Tianjin Key Laboratory of Metabolic Diseases (C.Z., T.Z., Z.C., M.Y., B.L., H.L., C.W., Y.Z., D.A.), Tianjin Medical Univer
  • Li B; State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) and Department of Physiology and Pathophysiology, Tianjin Key Laboratory of Metabolic Diseases (C.Z., T.Z., Z.C., M.Y., B.L., H.L., C.W., Y.Z., D.A.), Tianjin Medical Univer
  • Lv H; State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) and Department of Physiology and Pathophysiology, Tianjin Key Laboratory of Metabolic Diseases (C.Z., T.Z., Z.C., M.Y., B.L., H.L., C.W., Y.Z., D.A.), Tianjin Medical Univer
  • Wang C; National Clinical Research Center for Blood Diseases; Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (H.L., L.S., D.A.).
  • Xiang S; State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) and Department of Physiology and Pathophysiology, Tianjin Key Laboratory of Metabolic Diseases (C.Z., T.Z., Z.C., M.Y., B.L., H.L., C.W., Y.Z., D.A.), Tianjin Medical Univer
  • Shi L; Department of Biochemistry and Molecular Biology (S.X., L.S.), Tianjin Medical University, China.
  • Zhu Y; Department of Biochemistry and Molecular Biology (S.X., L.S.), Tianjin Medical University, China.
  • Ai D; National Clinical Research Center for Blood Diseases; Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (H.L., L.S., D.A.).
Circ Res ; 127(8): 1074-1090, 2020 09 25.
Article em En | MEDLINE | ID: mdl-32673515
RATIONALE: Atherosclerosis preferentially occurs at specific sites of the vasculature where endothelial cells (ECs) are exposed to disturbed blood flow. Translocation of integrin α5 to lipid rafts promotes integrin activation and ligation, which is critical for oscillatory shear stress (OSS)-induced EC activation. However, the underlying mechanism of OSS promoted integrin α5 lipid raft translocation has remained largely unknown. OBJECTIVE: The objective of this study was to specify the mechanotransduction mechanism of OSS-induced integrin α5 translocation and subsequent EC activation. METHODS AND RESULTS: Mass spectrometry studies identified endothelial ANXA2 (annexin A2) as a potential carrier allowing integrin α5ß1 to traffic in response to OSS. Interference by siRNA of AnxA2 in ECs greatly decreased OSS-induced integrin α5ß1 translocation to lipid rafts, EC activation, and monocyte adhesion. Pharmacological and genetic inhibition of PTP1B (protein tyrosine phosphatase 1B) blunted OSS-induced integrin α5ß1 activation, which is dependent on Piezo1-mediated calcium influx in ECs. Furthermore, ANXA2 was identified as a direct substrate of activated PTP1B by mass spectrometry. Using bioluminescence resonance energy transfer assay, PTP1B-dephosphorylated ANXA2 at Y24 was found to lead to conformational freedom of the C-terminal core domain from the N-terminal domain of ANXA2. Immunoprecipitation assays showed that this unmasked ANXA2-C-terminal core domain specifically binds to an integrin α5 nonconserved cytoplasmic domain but not ß1. Importantly, ectopic lentiviral overexpression of an ANXA2Y24F mutant increased and shRNA against Ptp1B decreased integrin α5ß1 ligation, inflammatory signaling, and progression of plaques at atheroprone sites in apolipoprotein E (ApoE)-/- mice. However, the antiatherosclerotic effect of Ptp1B shRNA was abolished in AnxA2-/-ApoE-/- mice. CONCLUSIONS: Our data elucidate a novel endothelial mechanotransduction molecular mechanism linking atheroprone flow and activation of integrin α5ß1, thereby identifying a class of potential therapeutic targets for atherosclerosis. Graphic Abstract: An graphic abstract is available for this article.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Endotélio Vascular / Anexina A2 / Microdomínios da Membrana / Integrina alfa5beta1 / Integrina alfa5 / Células Endoteliais / Aterosclerose Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Endotélio Vascular / Anexina A2 / Microdomínios da Membrana / Integrina alfa5beta1 / Integrina alfa5 / Células Endoteliais / Aterosclerose Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2020 Tipo de documento: Article