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 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, versus 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% versus 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.

Remote Ischemic Conditioning

“…The stimulus can originate not only from local ischemia/reperfusion injury in an organ other than the heart (e.g., mesentery (12,14,37) or limb (35,38–42)), but also from local surgical trauma (18–20,41), local activation of sensory fibers by capsaicin (18,21,35), bradykinin (14,20), or adenosine (39), and local electrical nerve stimulation (21,23). Accordingly, local anesthesia with lidocaine (18) or a sensory nerve blocker (21) and transection of the peripheral nerve (21,35,39,40) abrogated protection by RIPC, although femoral nerve transection did not abrogate protection by limb RIPC in mice in one study (42).…”

“…The local release mechanism in response to a nociceptive stimulus involves protein kinase Cγ in rats (20) and is inhibited by a nitric oxide donor (39). Whereas the causal involvement of peripheral nociceptive sensory nerves is unequivocal, the nature and transfer to the heart of the released transmitter molecule through neuronal or humoral pathways remains ambiguous.…”

Molecular Basis of Cardioprotection

“…The activation of the peripheral sensory fibers involves activation of the PKCγ isoform. 439 In some studies, activation of the autonomic nervous system through spinal and supraspinal reflexes [435][436][437]442 was mandatory to reduce IS in the ischemic/reperfused myocardium, 32,92,434,435,437,443 in others it was not. 432,444 Of importance, humoral transfer of protection with plasma or dialysate obtained after the peripheral preconditioning cycles to another individual or individual heart, even across species, is possible and highlights the functional importance of the humoral transfer signal.…”

Transient Receptor Potential Ankyrin 1 Activation within the Cardiac Myocyte Limits Ischemia–reperfusion Injury in Rodents

“…1 These drugs have serious unwanted side effects including abuse, dependence, and addiction. As a result, an opioid epidemic within the United States is shifting medical practice towards prescribing non-opioid analgesics or opioid adjuvants to reduce opioid use intraoperatively, postoperatively, and in the clinic.…”