deltaPKC participates in the endoplasmic reticulum stress-induced response in cultured cardiac myocytes and ischemic heart.
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 deltaPKC to the ER. We further demonstrate that inhibition of deltaPKC using the deltaPKC-specific antagonist peptide, deltaV1-1, 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 deltaPKC 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 deltaPKC 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 deltaPKC inhibition by deltaV1-1 blocks these events. Therefore, ischemia-reperfusion injury induces ER stress in the myocardium in a mechanism that requires deltaPKC activity. Taken together, our data show for the first time that deltaPKC activation plays a critical role in the ER stress-mediated response and the resultant cell death.
Qi
Xin
X
Department of Chemical and Systems Biology, Stanford University School of Medicine, CCSR, Room 3145A, 269 Campus Dr., Stanford, CA 94305, USA.
Vallentin
Alice
A
Churchill
Eric
E
Mochly-Rosen
Daria
D
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D008297:Male; D017202:Myocardial Ischemia / Q000201:enzymology / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013312:Stress, Physiological / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D014415:Tunicamycin / Q000494:pharmacology