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Endoplasmic Reticulum Chaperone GRP78 Protects Heart From Ischemia/Reperfusion Injury Through Akt Activation.
Bi, Xukun; Zhang, Guangyu; Wang, Xiaoding; Nguyen, Chau; May, Herman I; Li, Xiaoting; Al-Hashimi, Ali A; Austin, Richard C; Gillette, Thomas G; Fu, Guosheng; Wang, Zhao V; Hill, Joseph A.
Afiliación
  • Bi X; From the Department of Cardiology, Biomedical Research (Therapy) Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China (X.B., X.L., G.F.).
  • Zhang G; Division of Cardiology, Department of Internal Medicine (X.B., G.Z., X.W., C.N., H.I.M., T.G.G., Z.V.W., J.A.H.).
  • Wang X; Division of Cardiology, Department of Internal Medicine (X.B., G.Z., X.W., C.N., H.I.M., T.G.G., Z.V.W., J.A.H.).
  • Nguyen C; University of Texas Southwestern Medical Center, Dallas; Department of Cardiology, Zhongnan Hospital of Wuhan University, Hubei, China (G.Z.).
  • May HI; Division of Cardiology, Department of Internal Medicine (X.B., G.Z., X.W., C.N., H.I.M., T.G.G., Z.V.W., J.A.H.).
  • Li X; Department of Cardiology, Renmin Hospital of Wuhan University, Hubei, China (X.W.).
  • Al-Hashimi AA; Division of Cardiology, Department of Internal Medicine (X.B., G.Z., X.W., C.N., H.I.M., T.G.G., Z.V.W., J.A.H.).
  • Austin RC; Division of Cardiology, Department of Internal Medicine (X.B., G.Z., X.W., C.N., H.I.M., T.G.G., Z.V.W., J.A.H.).
  • Gillette TG; From the Department of Cardiology, Biomedical Research (Therapy) Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China (X.B., X.L., G.F.).
  • Fu G; Department of Medicine, Hamilton Center for Kidney Research, McMaster University and the Research Institute of St. Joseph's Healthcare Hamilton, ON, Canada (A.A.A.-H., R.C.A.).
  • Wang ZV; Department of Medicine, Hamilton Center for Kidney Research, McMaster University and the Research Institute of St. Joseph's Healthcare Hamilton, ON, Canada (A.A.A.-H., R.C.A.).
  • Hill JA; Division of Cardiology, Department of Internal Medicine (X.B., G.Z., X.W., C.N., H.I.M., T.G.G., Z.V.W., J.A.H.).
Circ Res ; 122(11): 1545-1554, 2018 05 25.
Article en En | MEDLINE | ID: mdl-29669712
RATIONALE: Restoration of coronary artery blood flow is the most effective means of ameliorating myocardial damage triggered by ischemic heart disease. However, coronary reperfusion elicits an increment of additional injury to the myocardium. Accumulating evidence indicates that the unfolded protein response (UPR) in cardiomyocytes is activated by ischemia/reperfusion (I/R) injury. Xbp1s (spliced X-box binding protein 1), the most highly conserved branch of the unfolded protein response, is protective in response to cardiac I/R injury. GRP78 (78 kDa glucose-regulated protein), a master regulator of the UPR and an Xbp1s target, is upregulated after I/R. However, its role in the protective response of Xbp1s during I/R remains largely undefined. OBJECTIVE: To elucidate the role of GRP78 in the cardiomyocyte response to I/R using both in vitro and in vivo approaches. METHODS AND RESULTS: Simulated I/R injury to cultured neonatal rat ventricular myocytes induced apoptotic cell death and strong activation of the UPR and GRP78. Overexpression of GRP78 in neonatal rat ventricular myocytes significantly protected myocytes from I/R-induced cell death. Furthermore, cardiomyocyte-specific overexpression of GRP78 ameliorated I/R damage to the heart in vivo. Exploration of underlying mechanisms revealed that GRP78 mitigates cellular damage by suppressing the accumulation of reactive oxygen species. We go on to show that the GRP78-mediated cytoprotective response involves plasma membrane translocation of GRP78 and interaction with PI3 kinase, culminating in stimulation of Akt. This response is required as inhibition of the Akt pathway significantly blunted the antioxidant activity and cardioprotective effects of GRP78. CONCLUSIONS: I/R induction of GRP78 in cardiomyocytes stimulates Akt signaling and protects against oxidative stress, which together protect cells from I/R damage.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Daño por Reperfusión Miocárdica / Isquemia Miocárdica / Miocitos Cardíacos / Proteínas Proto-Oncogénicas c-akt / Respuesta de Proteína Desplegada / Proteínas de Choque Térmico Tipo de estudio: Etiology_studies Límite: Animals Idioma: En Revista: Circ Res Año: 2018 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Daño por Reperfusión Miocárdica / Isquemia Miocárdica / Miocitos Cardíacos / Proteínas Proto-Oncogénicas c-akt / Respuesta de Proteína Desplegada / Proteínas de Choque Térmico Tipo de estudio: Etiology_studies Límite: Animals Idioma: En Revista: Circ Res Año: 2018 Tipo del documento: Article Pais de publicación: Estados Unidos