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

Abstract

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.

PKCδ Is Activated in a Dietary Model of Steatohepatitis and Regulates Endoplasmic Reticulum Stress and Cell Death

“…This observation extends our recent findings that a reduction in PKC␦ protein content blunted thapsigargin-stimulated JNK activation and CHOP protein induction (19). Tunicamycin-stimulated JNK activation is also blunted in Neuro2a cells with reduced PKC␦ protein expression (52). Taken together, these data indicate that PKC␦ may play a role in the propagation of the ER stress signal.…”

Novel Roles for Protein Kinase C;-dependent Signaling Pathways in Acute Hypoxic Stress-induced Autophagy

“…The importance of time-dependent PKC␦ activation in differential cell fate determination is further supported by the report that PKC␦ plays a role in mediating endoplasmic reticulum (ER) stress in ischemic heart (46). Intriguingly, there is an intricate relationship between ER stress and autophagy.…”

A novel endoplasmic reticulum stress-induced apoptosis model using tunicamycin in primary cultured neonatal rat cardiomyocytes

“…Therefore, the present study aimed to establish an ER stress-induced apoptotic model using tunicamycin in primary cultured neonatal rat cardiomyocytes. Although tunicamycin has been used to induce ER stress in other cell types, cells are often regulated in a typeand stimulus-specific manner (27,28). Therefore, in order to screen the optimal treatment time and concentration of ER stress-induced cell injury by tunicamycin in cardiomyocytes, cell viability was assessed by an MTT assay, and cardiomyocyte injury was detected using an LDH release assay.…”