Endoplasmic Reticulum Chaperone GRP78 Protects Heart from Ischemia/Reperfusion Injury Through Akt Activation

Xukun Bi, Guangyu Zhang, Xiaoding Wang, Chau Nguyen, Herman I. May, Xiaoting Li, Ali A. Al-Hashimi, Richard C. Austin, Thomas G. Gillette, Guosheng Fu, Zhao Wang, Joseph A Hill

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1545-1554
Number of pages10
JournalCirculation Research
Volume122
Issue number11
DOIs
StatePublished - May 25 2018

Fingerprint

Reperfusion Injury
Endoplasmic Reticulum
Unfolded Protein Response
Ischemia
Cardiac Myocytes
Reperfusion
Muscle Cells
Cell Death
Myocardial Reperfusion
Phosphatidylinositol 3-Kinases
Myocardial Ischemia
Reactive Oxygen Species
Coronary Vessels
Myocardium
Oxidative Stress
Antioxidants
Cell Membrane
Wounds and Injuries

Keywords

  • cell death
  • myocardium
  • reactive oxygen species
  • reperfusion injury
  • unfolded protein response

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

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; Hill, Joseph A.

In: Circulation Research, Vol. 122, No. 11, 25.05.2018, p. 1545-1554.

Research output: Contribution to journalArticle

Bi, X, Zhang, G, Wang, X, Nguyen, C, May, HI, Li, X, Al-Hashimi, AA, Austin, RC, Gillette, TG, Fu, G, Wang, Z & Hill, JA 2018, 'Endoplasmic Reticulum Chaperone GRP78 Protects Heart from Ischemia/Reperfusion Injury Through Akt Activation', Circulation Research, vol. 122, no. 11, pp. 1545-1554. https://doi.org/10.1161/CIRCRESAHA.117.312641
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 ; Hill, Joseph A. / Endoplasmic Reticulum Chaperone GRP78 Protects Heart from Ischemia/Reperfusion Injury Through Akt Activation. In: Circulation Research. 2018 ; Vol. 122, No. 11. pp. 1545-1554.
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AU - Bi, Xukun

AU - Zhang, Guangyu

AU - Wang, Xiaoding

AU - Nguyen, Chau

AU - May, Herman I.

AU - Li, Xiaoting

AU - Al-Hashimi, Ali A.

AU - Austin, Richard C.

AU - Gillette, Thomas G.

AU - Fu, Guosheng

AU - Wang, Zhao

AU - Hill, Joseph A

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AB - 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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KW - reactive oxygen species

KW - reperfusion injury

KW - unfolded protein response

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