Activation of the Unfolded Protein Response in Infarcted Mouse Heart and Hypoxic Cultured Cardiac Myocytes

Thuerauf, Donna J.; Marcinko, Marie; Gude, Natalie; Rubio, Marta; Sussman, Mark A.; Glembotski, Christopher C.

doi:10.1161/01.res.0000233317.70421.03

Cited by 275 publications

(274 citation statements)

References 48 publications

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“…Hypoxia induces the expression of XBP1 splicing and GRP78 in cultures of rat neonatal cardiac myocytes [5,8]. In a mouse model of myocardial infarction, an increased expression of GRP78 was observed in cells near the infarct four days after occlusion of the left anterior descending coronary artery [5]. However, in our study, we found that the levels of GRP878 increased after 35 min ischemia followed by 60 min of reperfusion and after 24 hours of Tm treatment in cultured myocytes.…”

Section: Discussioncontrasting

confidence: 75%

“…However, few studies have investigated the role of ER stress in the induction of apoptosis during ischemia/ reperfusion. Hypoxia induces the expression of XBP1 splicing and GRP78 in cultures of rat neonatal cardiac myocytes [5,8]. In a mouse model of myocardial infarction, an increased expression of GRP78 was observed in cells near the infarct four days after occlusion of the left anterior descending coronary artery [5].…”

Section: Discussionmentioning

confidence: 98%

“…δPKC translocation to the ER mediates, at least in part, ER stress response of the myocardium in a model of ischemia-reperfusion injury Inhibition of δPKC protects the heart from ischemia-reperfusion injury partly through reducing mitochondria-mediated cell death [13,16]. Increasing evidence suggests that ischemia/ reperfusion in the heart also activates the ER stress response resulting in cellular injury [5,8,9,[30][31][32]. Based on our in vitro results, we next determined whether inhibition of δPKC protects the myocardium from ER stress in an ex vivo model of ischemia and reperfusion injury.…”

Section: δPkc Translocates To the Endoplasmic Reticulum Following Tunmentioning

confidence: 99%

“…However, there is an increasing evidence suggesting that UPR may be activated in cardiac myocytes and expression of ER chaperone proteins increases in a rat model of pressure overload [5,6].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, recent evidence suggests that cardiac ischemia and hypoxia induce UPR [5,8,9]. Elevated UPR response is found in isolated cardiac myocytes subjected to hypoxia, as well as in a mouse model of myocardial infarction.…”

Section: Introductionmentioning

confidence: 99%

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δPKC participates in the endoplasmic reticulum stress-induced response in cultured cardiac myocytes and ischemic heart

Vallentin

Churchill

et al. 2007

Journal of Molecular and Cellular Cardiology

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The cellular response to excessive endoplasmic reticulum (ER) stress includes the activation of signaling pathways, which lead to apoptotic cell death. Here we show that treatment of cultured cardiac myocytes with tunicamycin, an agent that induces ER stress, causes the rapid translocation of δPKC to the ER. We further demonstrate that inhibition of δPKC using the δPKC-specific antagonist peptide, δV1-1, reduces tunicamycin-induced apoptotic cell death, and inhibits expression of specific ER stress response markers such as CHOP, GRP78 and phosphorylation of JNK. The physiological importance of δPKC in this event is further supported by our findings that the ER stress response is also induced in hearts subjected to ischemia and reperfusion injury and that this response also involves δPKC translocation to the ER. We found that the levels of the ER chaperone, GRP78, the spliced XBP-1 and the phosphorylation of JNK are all increased following ischemia and reperfusion and that δPKC inhibition by δV1-1 blocks these events. Therefore, ischemia-reperfusion injury induces ER stress in the myocardium in a mechanism that requires δPKC activity. Taken together, our data show for the first time that δPKC activation plays a critical role in the ER stressmediated response and the resultant cell death.

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Section: Discussioncontrasting

confidence: 75%

Section: Discussionmentioning

confidence: 98%

Section: δPkc Translocates To the Endoplasmic Reticulum Following Tunmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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δPKC participates in the endoplasmic reticulum stress-induced response in cultured cardiac myocytes and ischemic heart

Vallentin

Churchill

et al. 2007

Journal of Molecular and Cellular Cardiology

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A review of the mammalian unfolded protein response

Chakrabarti

Chen

Varner

2011

Biotech & Bioengineering

362

331

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Proteins requiring post-translational modifications such as N-linked glycosylation are processed in the endoplasmic reticulum (ER). A diverse array of cellular stresses can lead to dysfunction of the ER and ultimately to an imbalance between protein-folding capacity and protein-folding load. Cells monitor protein folding by an inbuilt quality control system involving both the ER and the Golgi apparatus. Unfolded or misfolded proteins are tagged for degradation via ER associated degradation (ERAD) or sent back through the folding cycle. Continued accumulation of incorrectly folded proteins can also trigger the Unfolded Protein Response (UPR). In mammalian cells, UPR is a complex signaling program mediated by three ER transmembrane receptors: activating transcription factor 6 (ATF6), inositol requiring kinase 1 (IRE1) and double-stranded RNA-activated protein kinase (PKR)-like endoplasmic reticulum kinase (PERK). UPR performs three functions, adaptation, alarm and apoptosis. During adaptation, the UPR tries to reestablish folding homeostasis by inducing the expression of chaperones that enhance protein folding. Simultaneously, global translation is attenuated to reduce the ER folding load while the degradation rate of unfolded proteins is increased. If these steps fail, the UPR induces a cellular alarm and mitochondrial mediated apoptosis program. UPR malfunctions have been associated with a wide range of disease states including tumor progression, diabetes, as well as immune and inflammatory disorders. This review describes recent advances in understanding the molecular structure of UPR in mammalian cells, its functional role in cellular stress, and its pathophysiology.

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Thioredoxin Superfamily and Its Effects on Cardiac Physiology and Pathology

Yoshioka

2015

Comprehensive Physiology

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A precise control of oxidation/reduction of protein thiols is essential for intact cardiac physiology. Irreversible oxidative modifications have been proposed to play a role in the pathogenesis of cardiovascular diseases. An imbalance of redox homeostasis with diminution of antioxidant capacities predisposes the heart to oxidant injury. There is growing interest in endoplasmic reticulum (ER) stress in the cardiovascular field, since perturbation of redox homeostasis in the ER is sufficient to cause ER stress. Because a number of human diseases are related to altered redox homeostasis and defects in protein folding, many research efforts have been devoted in recent years to understanding the structure and enzymatic properties of the thioredoxin superfamily. The thioredoxin superfamily has been well documented as thiol oxidoreductases to exert a role in various cell signaling pathways. The redox properties of the thioredoxin motif account for the different functions of several members of the thioredoxin superfamily. While thioredoxin and glutaredoxin primarily act as antioxidants by reducing protein disulfides and mixed disulfide, another member of the superfamily, protein disulfide isomerase (PDI), can act as an oxidant by forming intrachain disulfide bonds that contribute to proper protein folding. Increasing evidence suggests a pivotal role of PDI in the survival pathway that promotes cardiomyocyte survival and leads to more favorable cardiac remodeling. Thus, the thiol redox state is important for cellular redox signaling and survival pathway in the heart. This review summarizes the key features of major members of the thioredoxin superfamily directly involved in cardiac physiology and pathology.

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Activation of the Unfolded Protein Response in Infarcted Mouse Heart and Hypoxic Cultured Cardiac Myocytes

Cited by 275 publications

References 48 publications

δPKC participates in the endoplasmic reticulum stress-induced response in cultured cardiac myocytes and ischemic heart

δPKC participates in the endoplasmic reticulum stress-induced response in cultured cardiac myocytes and ischemic heart

A review of the mammalian unfolded protein response

Thioredoxin Superfamily and Its Effects on Cardiac Physiology and Pathology

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