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Abstract
Deciphering the remote conditioning molecular mechanism may provide targets to develop therapeutics that can broaden the clinical application. To further investigate this, we tested whether two protein kinase C (PKC) isozymes, the ubiquitously expressed epsilon PKC (ePKC) and the neuronal-specific gamma PKC (?PKC), mediate nociceptive-induced remote myocardial conditioning. Male Sprague-Dawley rats were used for both in vivo and ex vivo myocardial ischemia-reperfusion protocols. For the in vivo studies, using a surgical abdominal incision for comparison, applying only to the abdomen either bradykinin or the ePKC activator (?eRACK) reduced myocardial infarct size (45 ± 1, 44 ± 2 %, respectively, vs. incision: 43 ± 2 %, and control: 63 ± 2 %, P < 0.001). Western blot showed only ePKC, and not ?PKC, is highly expressed in the myocardium. However, applying a selective ?PKC inhibitor (?V5-3) to the abdominal skin blocked remote protection by any of these strategies. Using an ex vivo isolated heart model without an intact nervous system, only selective ePKC activation, unlike a selective classical PKC isozyme activator (activating a, ß, ßII, and ?), reduced myocardial injury. Importantly, the classical PKC isozyme activator given to the abdomen in vivo (with an intact nervous system including ?PKC) during myocardial ischemia reduced infarct size as effectively as an abdominal incision or ?eRACK (45 ± 1 vs. 45 ± 2 and 47 ± 1 %, respectively). The classical PKC activator-induced protection was also blocked by spinal cord surgical transection. These findings identified potential remote conditioning mimetics, with these strategies effective even during myocardial ischemia. A novel mechanism of nociceptive-induced remote conditioning, involving ?PKC, was also identified.
View details for DOI 10.1007/s00395-013-0381-x
View details for PubMedID 23982492