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

Bi, Xiwen; Zhang, Guangyu; Wang, Xiaoding; Nguyen, Chau Yt; May, Herman I.; Li, Xiaoting; Al‐Hashimi, Ali; Austin, Richard C.; Gillette, Thomas G.; Guo, Fu; Wang, Zhao V.; Hill, Joseph A.

doi:10.1161/circresaha.117.312641

Cited by 119 publications

(102 citation statements)

References 81 publications

(104 reference statements)

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“…Finally, a very strong response by Grp78 was seen in wood frog heart, ~3.3‐fold increase, in response to both anoxia and dehydration. This seemingly anomalous effect may represent a conserved response to ischemia that has recently be reported for mammalian heart (Bi et al, ). These authors showed that the UPR and Grp78 expression was triggered in heart in response to ischemia/reperfusion and that overexpression of Grp78 and its translocation to the plasma membrane in vitro in cardiomyocytes ameliorated I/R‐induced cell death by suppressing reactive oxygen species formation.…”

Section: Discussionsupporting

confidence: 60%

In defense of proteins: Chaperones respond to freezing, anoxia, or dehydration stress in tissues of freeze tolerant wood frogs

Storey

2019

J Exp Zool Pt A

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Wood frogs (Rana sylvatica LeConte) are the major model for studies of natural freeze tolerance by ectothermic vertebrates. Multiple biochemical adaptations support winter freezing survival but, to date, the protective role of chaperone proteins has received little attention. The present study analyzes responses to freezing, anoxia or dehydration exposures and recovery from these stresses by chaperone proteins in six wood frog organs: Five heat shock proteins (Hsc70, Hsp110, Hsp60, Hsp40, and Hsp10) and two glucose‐regulated proteins (Grp78 and Grp94) were assessed. Hsc70 was upregulated in liver, muscle, heart and kidney (1.5–2.0 fold) during freezing and levels of its partner proteins also rose (Hsp110 in three tissues and Hsp40 in four tissues), these responses aligning most closely with comparable responses to anoxia rather than to dehydration. The resident chaperones of the endoplasmic reticulum (Grp78 and Grp94) also rose during freezing in liver and muscle (1.4–1.8 fold) but were suppressed in heart and skin, patterns that generally differed from responses to anoxia or dehydration. Elevated GRPs in liver may support the production and secretion of novel freeze responsive proteins. Increased levels of mitochondrial Hsp60 and Hsp10 (1.5–2.2 fold) occurred in most tissues during freezing and generally mimicked responses to anoxia. Overall, this study indicates that increased levels of chaperone proteins resident in multiple subcellular compartments contribute to stabilizing the cellular proteome during whole body freezing of wood frogs. These responses are probably derived from pre‐existing amphibian defenses for stabilizing the proteome under environmental low oxygen or dehydration stresses.

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Section: Discussionsupporting

confidence: 60%

In defense of proteins: Chaperones respond to freezing, anoxia, or dehydration stress in tissues of freeze tolerant wood frogs

Storey

2019

J Exp Zool Pt A

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“…3, Table 2). The activation of ER stress has been reported as well in different critical care diseases models, such as sepsis [331,332], liver, heart, brain and kidney ischaemia [353][354][355][356][357][358][359] and haemorrhagic shock [334,335]. But, the pathophysiological impact of ER stress activation in these conditions severely lacks characterization.…”

Section: Er Stress and Upr-based Therapiesmentioning

confidence: 99%

Endoplasmic reticulum stress signalling – from basic mechanisms to clinical applications

et al. 2018

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The endoplasmic reticulum (ER) is a membranous intracellular organelle and the first compartment of the secretory pathway. As such, the ER contributes to the production and folding of approximately one-third of cellular proteins, and is thus inextricably linked to the maintenance of cellular homeostasis and the fine balance between health and disease. Specific ER stress signalling pathways, collectively known as the unfolded protein response (UPR), are required for maintaining ER homeostasis. The UPR is triggered when ER protein folding capacity is overwhelmed by cellular demand and the UPR initially aims to restore ER homeostasis and normal cellular functions. However, if this fails, then the UPR triggers cell death. In this review, we provide a UPR signalling-centric view of ER functions, from the ER's discovery to the latest advancements in the understanding of ER and UPR biology. Our review provides a synthesis of intracellular ER signalling revolving around proteostasis and the UPR, its impact on other organelles and cellular behaviour, its multifaceted and dynamic response to stress and its role in physiology, before finally exploring the potential exploitation of this knowledge to tackle unresolved biological questions and address unmet biomedical needs. Thus, we provide an integrated and global view of existing literature on ER signalling pathways and their use for therapeutic purposes.

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“…In accordance with the results in vivo, levels of FAK/AKT signaling pathway molecules were increased or decreased after ADAM23 knockdown or overexpression in AngII–treated NRCMs (Figure 5C). Given that FAK/AKT signaling was associated with cardiomyocyte death,24, 25 terminal deoxynucleotidyl transferase‐mediated dUTP nick end‐labeling assay and Western blot analysis for cleaved caspase 3 were performed to assess whether ADAM23 regulates the cell death process in response to pressure overload. However, neither ADAM23 deletion nor ADAM23 overexpression in the heart affects cardiomyocyte death after AB surgery, as compared with their corresponding controls (Figure S5A and S5B).…”

Section: Resultsmentioning

confidence: 99%

ADAM23 in Cardiomyocyte Inhibits Cardiac Hypertrophy by Targeting FAK‐AKT Signaling

Xiang

Luo

et al. 2018

JAHA

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BackgroundCardiac hypertrophy has been recognized as an important independent risk factor for the development of heart failure and increases the risk of cardiac morbidity and mortality. A disintegrin and metalloprotease 23 (ADAM23), a member of ADAM family, is involved in cancer and neuronal differentiation. Although ADAM23 is expressed in the heart, the role of ADAM23 in the heart and in cardiac diseases remains unknown.Methods and ResultsWe observed that ADAM23 expression is decreased in both failing human hearts and hypertrophic mice hearts. Cardiac‐specific conditional ADAM23‐knockout mice significantly exhibited exacerbated cardiac hypertrophy, fibrosis, and dysfunction, whereas transgenic mice overexpressing ADAM23 in the heart exhibited reduced cardiac hypertrophy in response to pressure overload. Consistent results were also observed in angiotensin II‐induced neonatal rat cardiomyocyte hypertrophy. Mechanistically, ADAM23 exerts anti‐hypertrophic effects by specifically targeting the focal adhesion kinase‐protein kinase B (FAK‐AKT) signaling cascade. Focal adhesion kinase inactivation by inhibitor (PF‐562271) greatly reversed the detrimental effects in ADAM23‐knockout mice subjected to aortic banding.ConclusionAltogether, we identified ADAM23 as a negative regulator of cardiac hypertrophy through inhibiting focal adhesion kinase‐protein kinase B signaling pathway, which could be a promising therapeutic target for this malady.

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

Abstract: I/R induction of GRP78 in cardiomyocytes stimulates Akt signaling and protects against oxidative stress, which together protect cells from I/R damage.

Cited by 119 publications

References 81 publications

In defense of proteins: Chaperones respond to freezing, anoxia, or dehydration stress in tissues of freeze tolerant wood frogs

In defense of proteins: Chaperones respond to freezing, anoxia, or dehydration stress in tissues of freeze tolerant wood frogs

Endoplasmic reticulum stress signalling – from basic mechanisms to clinical applications

ADAM23 in Cardiomyocyte Inhibits Cardiac Hypertrophy by Targeting FAK‐AKT Signaling

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