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Nociceptive-induced myocardial remote conditioning is mediated by neuronal gamma protein kinase C

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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 (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.

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References

  1. Aronowski J, Grotta JC, Strong R, Waxham MN (2000) Interplay between the gamma isoform of PKC and calcineurin in regulation of vulnerability to focal cerebral ischemia. J Cereb Blood Flow Metab 20:343–349. doi:10.1097/00004647-200002000-00016

    Article  PubMed  CAS  Google Scholar 

  2. Budas GR, Churchill EN, Mochly-Rosen D (2007) Cardioprotective mechanisms of PKC isozyme-selective activators and inhibitors in the treatment of ischemia-reperfusion injury. Pharmacol Res 55:523–536

    Article  PubMed  CAS  Google Scholar 

  3. Budas GR, Churchill EN, Disatnik MH, Sun L, Mochly-Rosen D (2010) Mitochondrial import of PKCε is mediated by HSP90: a role in cardioprotection from ischemia and reperfusion injury. Cardiovasc Res. doi:10.1093/cvr/cvq154

    PubMed  Google Scholar 

  4. Cesare P, Dekker LV, Sardini A, Parker PJ, McNaughton PA (1999) Specific involvement of PKC-epsilon in sensitization of the neuronal response to painful heat. Neuron 23:617–624

    Article  PubMed  CAS  Google Scholar 

  5. Chen C, Kano M, Abeliovich A, Chen L, Bao S, Kim JJ, Hashimoto K, Thompson RF, Tonegawa S (1995) Impaired motor coordination correlates with persistent multiple climbing fiber innervation in PKC gamma mutant mice. Cell 83:1233–1242. doi:10.1016/0092-8674(95)90148-5

    Article  PubMed  CAS  Google Scholar 

  6. Chen CH, Budas GR, Churchill EN, Disatnik MH, Hurley TD, Mochly-Rosen D (2008) Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart. Science 321:1493–1495. doi:10.1126/science.1158554

    Article  PubMed  CAS  Google Scholar 

  7. Chen L, Hahn H, Wu G, Chen CH, Liron T, Schechtman D, Cavallaro G, Banci L, Guo Y, Bolli R, Dorn GW 2nd, Mochly-Rosen D (2001) Opposing cardioprotective actions and parallel hypertrophic effects of delta PKC and epsilon PKC. Proc Natl Acad Sci 98:11114–11119. doi:10.1073/pnas.191369098

    Article  PubMed  CAS  Google Scholar 

  8. Contractor H, Stottrup NB, Cunnington C, Manlhiot C, Diesch J, Ormerod JO, Jensen R, Botker HE, Redington A, Schmidt MR, Ashrafian H, Kharbanda RK (2013) Aldehyde dehydrogenase-2 inhibition blocks remote preconditioning in experimental and human models. Basic Res Cardiol 108:343. doi:10.1007/s00395-013-0343-3

    Article  PubMed  Google Scholar 

  9. Cui W, Li Y, Li S, Yang W, Jiang J, Han S, Li J (2009) Systemic lidocaine inhibits remifentanil-induced hyperalgesia via the inhibition of cPKCgamma membrane translocation in spinal dorsal horn of rats. J Neurosurg Anesthesiol 21:318–325. doi:10.1097/ANA.0b013e3181abbde5

    Article  PubMed  Google Scholar 

  10. Dalski A, Mitulla B, Burk K, Schattenfroh C, Schwinger E, Zuhlke C (2006) Mutation of the highly conserved cysteine residue 131 of the SCA14 associated PRKCG gene in a family with slow progressive cerebellar ataxia. J Neurol 253:1111–1112. doi:10.1007/s00415-006-0209-9

    Article  PubMed  CAS  Google Scholar 

  11. Dorn GW 2nd, Souroujon MC, Liron T, Chen CH, Gray MO, Zhou HZ, Csukai M, Wu G, Lorenz JN, Mochly-Rosen D (1999) Sustained in vivo cardiac protection by a rationally designed peptide that causes epsilon protein kinase C translocation. Proc Natl Acad Sci 96:12798–12803. doi:10.1073/pnas96.22.12798

    Article  PubMed  CAS  Google Scholar 

  12. Ferguson RE, Carroll HP, Harris A, Maher ER, Selby PJ, Banks RE (2005) Housekeeping proteins: a preliminary study illustrating some limitations as useful references in protein expression studies. Proteomics 5:566–571. doi:10.1002/pmic.200400941

    Article  PubMed  CAS  Google Scholar 

  13. Ferreira JC, Boer BN, Grinberg M, Brum PC, Mochly-Rosen D (2012) Protein quality control disruption by PKCbetaII in heart failure; rescue by the selective PKCbetaII inhibitor, betaIIV5-3. PLoS ONE 7:e33175. doi:10.1371/journal.pone.0033175

    Article  PubMed  CAS  Google Scholar 

  14. Gray MO, Karliner JS, Mochly-Rosen D (1997) A selective ε-protein kinase C antagonist inhibits protection of cardiac myocytes from hypoxia-induced cell death. J Biol Chem 272:30945–30951. doi:10.1074/jbc.272.49.30945

    Article  PubMed  CAS  Google Scholar 

  15. Gross ER, Hsu AK, Gross GJ (2007) GSK3beta inhibition and K(ATP) channel opening mediate acute opioid-induced cardioprotection at reperfusion. Basic Res Cardiol 102:341–349. doi:10.1007/s00395-007-0651-6

    Article  PubMed  CAS  Google Scholar 

  16. Gross GJ, Baker JE, Moore J, Falck JR, Nithipatikom K (2011) Abdominal surgical incision induces remote preconditioning of trauma (RPCT) via activation of bradykinin receptors (BK2R) and the cytochrome P450 epoxygenase pathway in canine hearts. Cardiovasc Drugs Ther 25:517–522. doi:10.1007/s10557-011-6321-9

    Article  PubMed  CAS  Google Scholar 

  17. Gross GJ, Hsu A, Gross ER, Falck JR, Nithipatikom K (2012) Factors mediating remote preconditioning of trauma in the rat heart: central role of the cytochrome P450 epoxygenase pathway in mediating infarct size reduction. J Cardiovasc Pharmacol Ther 38–45. doi:10.1177/1074248412437586

  18. Hambleton M, Hahn H, Pleger ST, Kuhn MC, Klevitsky R, Carr AN, Kimball TF, Hewett TE, Dorn GW 2nd, Koch WJ, Molkentin JD (2006) Pharmacological- and gene therapy-based inhibition of protein kinase Calpha/beta enhances cardiac contractility and attenuates heart failure. Circulation 114:574–582. doi:10.1161/CIRCULATIONAHA.105.592550

    Article  PubMed  CAS  Google Scholar 

  19. Hayashi S, Ueyama T, Kajimoto T, Yagi K, Kohmura E, Saito N (2005) Involvement of gamma protein kinase C in estrogen-induced neuroprotection against focal brain ischemia through G protein-coupled estrogen receptor. J Neurochem 93:883–891. doi:10.1111/j.1471-4159.2005.03080.x

    Article  PubMed  CAS  Google Scholar 

  20. Heusch G, Musiolik J, Kottenberg E, Peters J, Jakob H, Thielmann M (2012) STAT5 activation and cardioprotection by remote ischemic preconditioning in humans: short communication. Circ Res 110:111–115. doi:10.1161/CIRCRESAHA.111.259556

    Article  PubMed  CAS  Google Scholar 

  21. Heusch G (2013) Cardioprotection: chances and challenges of its translation to the clinic. Lancet 381:166–175. doi:10.1016/S0140-6736(12)60916-7

    Article  PubMed  Google Scholar 

  22. Inagaki K, Hahn HS, Dorn GW 2nd, Mochly-Rosen D (2003) Additive protection of the ischemic heart ex vivo by combined treatment with delta-protein kinase C inhibitor and epsilon-protein kinase C activator. Circulation 108:869–875. doi:10.1161/01.CIR.0000081943.93653.73

    Article  PubMed  CAS  Google Scholar 

  23. Inagaki K, Begley R, Ikeno F, Mochly-Rosen D (2005) Cardioprotection by epsilon-protein kinase C activation from ischemia: continuous delivery and antiarrhythmic effect of an epsilon-protein kinase C-activating peptide. Circulation 111:44–50. doi:10.1161/01.CIR.0000151614.22282.F1

    Article  PubMed  CAS  Google Scholar 

  24. Jeske NA, Patwardhan AM, Ruparel NB, Akopian AN, Shapiro MS, Henry MA (2009) A-kinase anchoring protein 150 controls protein kinase C-mediated phosphorylation and sensitization of TRPV1. Pain 146:301–307. doi:10.1016/j.pain.2009.08.002

    Article  PubMed  CAS  Google Scholar 

  25. Jones WK, Fan GC, Liao S, Zhang JM, Wang Y, Weintraub NL, Kranias EG, Schultz JE, Lorenz J, Ren X (2009) Peripheral nociception associated with surgical incision elicits remote nonischemic cardioprotection via neurogenic activation of protein kinase C signaling. Circulation 120:S1–S9. doi:10.1161/CIRCULATIONAHA.108.843938

    Article  PubMed  CAS  Google Scholar 

  26. Li HF, Mochly-Rosen D, Kendig JJ (2005) Protein kinase Cγ mediates ethanol withdrawal hyper-responsiveness of NMDA receptor currents in spinal cord motor neurons. Br J Pharmacol 144:301–307. doi:10.1038/sj.bjp.0706033

    Article  PubMed  CAS  Google Scholar 

  27. Li LF, Fiedler VC, Kumar R (1998) Down-regulation of protein kinase C isoforms in irritant contact dermatitis. Contact Dermatitis 38:319–324

    Article  PubMed  CAS  Google Scholar 

  28. Lim SY, Yellon DM, Hausenloy DJ (2010) The neural and humoral pathways in remote limb ischemic preconditioning. Basic Res Cardiol 105:651–655. doi:10.1007/s00395-010-0099-y

    Article  PubMed  Google Scholar 

  29. Lin D, Barnett M, Lobell S, Madgwick D, Shanks D, Willard L, Zampighi GA, Takemoto DJ (2006) PKCγ knockout mouse lenses are more susceptible to oxidative stress damage. J Exp Biol 209:4371–4378. doi:10.1242/jeb.02524

    Article  PubMed  CAS  Google Scholar 

  30. Liu GS, Cohen MV, Mochly-Rosen D, Downey JM (1999) Protein kinase C-epsilon is responsible for the protection of preconditioning in rabbit cardiomyocytes. J Mol Cell Cardiol 31:1937–1948. doi:10.1006/jmcc.1999.1026S002228289991026X

    Article  PubMed  CAS  Google Scholar 

  31. Malmberg AB, Chen C, Tonegawa S, Basbaum AI (1997) Preserved acute pain and reduced neuropathic pain in mice lacking PKCγ. Science 278:279–283. doi:10.1126/science.278.5336.279

    Article  PubMed  CAS  Google Scholar 

  32. Mao J, Price DD, Phillips LL, Lu J, Mayer DJ (1995) Increases in protein kinase C gamma immunoreactivity in the spinal cord of rats associated with tolerance to the analgesic effects of morphine. Brain Res 677:257–267. doi:10.1016/0304-3940(95)11975-3

    Article  PubMed  CAS  Google Scholar 

  33. Miraucourt LS, Dallel R, Voisin DL (2007) Glycine inhibitory dysfunction turns touch into pain through PKCγ interneurons. PLoS ONE 2:e1116. doi:10.1371/journal.pone.0001116

    Article  PubMed  Google Scholar 

  34. Neumann S, Braz JM, Skinner K, Llewellyn-Smith IJ, Basbaum AI (2008) Innocuous, not noxious, input activates PKCγ interneurons of the spinal dorsal horn via myelinated afferent fibers. J Neurosci 28:7936–7944. doi:10.1523/JNEUROSCI.1259-08.2008

    Article  PubMed  CAS  Google Scholar 

  35. Peart JN, Gross ER, Reichelt ME, Hsu A, Headrick JP, Gross GJ (2008) Activation of κ-opioid receptors at reperfusion affords cardioprotection in both rat and mouse hearts. Basic Res Cardiol 103:454–463. doi:10.1007/s00395-008-0726-z

    Article  PubMed  CAS  Google Scholar 

  36. Polgar E, Fowler JH, McGill MM, Todd AJ (1999) The types of neuron which contain protein kinase C gamma in rat spinal cord. Brain Res 833:71–80. doi:10.1016/S0006-8993(99)01500-0

    Article  PubMed  CAS  Google Scholar 

  37. Qi X, Disatnik MH, Shen N, Sobel RA, Mochly-Rosen D (2011) Aberrant mitochondrial fission in neurons induced by protein kinase Cδ under oxidative stress conditions in vivo. Mol Biol Cell 22:256–265. doi:10.1091/mbc.E10-06-0551

    Article  PubMed  CAS  Google Scholar 

  38. Redington KL, Disenhouse T, Strantzas SC, Gladstone R, Wei C, Tropak MB, Dai X, Manlhiot C, Li J, Redington AN (2012) Remote cardioprotection by direct peripheral nerve stimulation and topical capsaicin is mediated by circulating humoral factors. Basic Res Cardiol 107:241. doi:10.1007/s00395-011-0241-5

    Article  PubMed  Google Scholar 

  39. Ron D, Chen CH, Caldwell J, Jamieson L, Orr E, Mochly-Rosen D (1994) Cloning of an intracellular receptor for protein kinase C: a homolog of the beta subunit of G proteins. Proc Natl Acad Sci 91:839–843. doi:10.1073/pnas91.3.839

    Article  PubMed  CAS  Google Scholar 

  40. Ron D, Luo J, Mochly-Rosen D (1995) C2 region-derived peptides inhibit translocation and function of beta protein kinase C in vivo. J Biol Chem 270:24180–24187. doi:10.1074/jbc.270.41.24180

    Article  PubMed  CAS  Google Scholar 

  41. Rybin VO, Steinberg SF (1994) Protein kinase C isoform expression and regulation in the developing rat heart. Circ Res 74:299–309

    Article  PubMed  CAS  Google Scholar 

  42. Schechtman D, Craske ML, Kheifets V, Meyer T, Schechtman J, Mochly-Rosen D (2004) A critical intramolecular interaction for protein kinase Cε translocation. J Biol Chem 279:15831–15840. doi:10.1074/jbc.M310696200

    Article  PubMed  CAS  Google Scholar 

  43. Skyschally A, van Caster P, Boengler K, Gres P, Musiolik J, Schilawa D, Schulz R, Heusch G (2009) Ischemic postconditioning in pigs: no causal role for RISK activation. Circ Res 104:15–18. doi:10.1161/CIRCRESAHA.108.186429

    Article  PubMed  CAS  Google Scholar 

  44. Souroujon MC, Mochly-Rosen D (1998) Peptide modulators of protein–protein interactions in intracellular signaling. Nat Biotechnol 16:919–924. doi:10.1038/nbt1098-919

    Article  PubMed  CAS  Google Scholar 

  45. Sweitzer SM, Wong SM, Peters MC, Mochly-Rosen D, Yeomans DC, Kendig JJ (2004) Protein kinase C ϵ and γ: involvement in formalin-induced nociception in neonatal rats. J Pharmacol Exp Ther 309:616–625. doi:10.1124/jpet.103.060350

    Article  PubMed  CAS  Google Scholar 

  46. Thielmann M, Kottenberg E, Boengler K, Raffelsieper C, Neuhaeuser M, Peters J, Jakob H, Heusch G (2010) Remote ischemic preconditioning reduces myocardial injury after coronary artery bypass surgery with crystalloid cardioplegic arrest. Basic Res Cardiol 105:657–664. doi:10.1007/s00395-010-0104-5

    Article  PubMed  CAS  Google Scholar 

  47. Vahlhaus C, Schulz R, Post H, Onallah R, Heusch G (1996) No prevention of ischemic preconditioning by the protein kinase C inhibitor staurosporine in swine. Circ Res 79:407–414

    Article  PubMed  CAS  Google Scholar 

  48. Wang Y, Wu J, Guo R, Zhao Y, Wang Y, Zhang M, Chen Z, Wu A, Yue Y (2013) Surgical incision induces phosphorylation of AMPA receptor GluR1 subunits at Serine-831 sites and GluR1 trafficking in spinal cord dorsal horn via a protein kinase Cγ-dependent mechanism. Neuroscience 240:361–370. doi:10.1016/j.neuroscience.2013.02.051

    Article  PubMed  CAS  Google Scholar 

  49. Wessendorf MW, Dooyema J (2001) Coexistence of κ- and δ-opioid receptors in rat spinal cord axons. Neurosci Lett 298:151–154. doi:10.1016/S0304-3940(00)01700-6

    Article  PubMed  CAS  Google Scholar 

  50. Xu TR, He G, Rumsby MG (2009) Adenosine triggers the nuclear translocation of protein kinase C epsilon in H9c2 cardiomyoblasts with the loss of phosphorylation at Ser729. J Cell Biochem 106:633–642. doi:10.1002/jcb.22043

    Article  PubMed  CAS  Google Scholar 

  51. Zhang N, Yin Y, Han S, Jiang J, Yang W, Bu X, Li J (2011) Hypoxic preconditioning induced neuroprotection against cerebral ischemic injuries and its cPKCγ-mediated molecular mechanism. Neurochem Int 58:684–692. doi:10.1016/j.neuint.2011.02.007

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This manuscript was supported in part by NIH HL52141 (DMR), NIH HL109212 (ERG), and NIH HL74314 (GJG). ERG, AKH, TJU and GJG have no disclosures. A preliminary US patent was filed based on findings in the manuscript.

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Authors and Affiliations

  1. Department of Anesthesiology, School of Medicine, Stanford University, Stanford, CA, 94305, USA

    Eric R. Gross & Travis J. Urban

  2. Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA

    Anna K. Hsu & Garrett J. Gross

  3. Department of Chemical and Systems Biology, School of Medicine, Stanford University, Stanford, CA, 94305-5174, USA

    Travis J. Urban & Daria Mochly-Rosen

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  1. Eric R. Gross
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Correspondence to Eric R. Gross.

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Gross, E.R., Hsu, A.K., Urban, T.J. et al. Nociceptive-induced myocardial remote conditioning is mediated by neuronal gamma protein kinase C. Basic Res Cardiol 108, 381 (2013). https://doi.org/10.1007/s00395-013-0381-x

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