title: Nociceptive-induced myocardial remote conditioning is mediated by neuronal gamma protein kinase C.
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 (εPKC) and the neuronal-specific gamma PKC (γPKC), 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 εPKC activator (ψεRACK) reduced myocardial infarct size (45 ± 1, 44 ± 2 %, respectively, vs. incision: 43 ± 2 %, and control: 63 ± 2 %, P < 0.001). Western blot showed only εPKC, and not γPKC, is highly expressed in the myocardium. However, applying a selective γPKC inhibitor (γV5-3) 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 εPKC activation, unlike a selective classical PKC isozyme activator (activating α, β, βII, and γ), reduced myocardial injury. Importantly, the classical PKC isozyme activator given to the abdomen in vivo (with an intact nervous system including γPKC) during myocardial ischemia reduced infarct size as effectively as an abdominal incision or ψεRACK (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 γPKC, was also identified.
authors: Department of Anesthesiology, School of Medicine, Stanford University, Stanford, CA 94305, USA. ergross@stanford.edu
authors: Eric R
authors: ER
authors: Gross
authors: Anna K
authors: AK
authors: Hsu
authors: Travis J
authors: TJ
authors: Urban
authors: Daria
authors: D
authors: Mochly-Rosen
authors: Garrett J
authors: GJ
authors: Gross
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control; D010146:Pain / Q000503:physiopathology*; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C087857:protein kinase C gamma; D011493:Protein Kinase C
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