Cardioprotection

Cardioprotection encompasses several regimens that have shown to preserve function and viability of cardiac muscle cell tissue subjected to ischemic insult or reoxygenation. Cardioprotection includes strategies that are implemented before an ischemic event (preconditioning, PC), during an ischemic event (perconditioning, PerC) and after the event and during reperfusion (postconditioning, PostC).[1] These strategies can be further stratified by performing the intervention locally or remotely, creating classes of conditioning known as remote ischemic PC (RIPC), remote ischemic PostC and remost ischemic PerC.[1] Classical (local) preconditioning has an early phase with an immediate onset lasting 2–3 hours that protects against myocardial infarction.[2] The early phase involves post-translational modification of preexisting proteins, brought about by the activation of G protein-coupled receptors as well as downstream MAPK’s and PI3/Akt. These signaling events act on the ROS-generating mitochondria, activate PKCε and the Reperfusion Injury Salvage Kinase (RISK) pathway, preventing mitochondrial permeability transition pore (MTP) opening.[3] The late phase with an onset of 12–24 hours that lasts 3–4 days and protects against both infarction and reversible postischemic contractile dysfunction, termed myocardial stunning.[4][5][6] This phase involves the synthesis of new cardioprotective proteins stimulated by nitric oxide (NO), ROS and adenosine acting on kinases such as PKCε and Src, which in turn activate gene transcription and upregulation of late PC molecular players (e.g., antioxidant enzymes, iNOS).[7]

A role for PKCε in more contemporary cardioprotection strategies including RIPC,[8] local PostC,[9] and remote PostC[10] have been either demonstrated or suggested. It was shown that PKCε translocates from the cytosolic to the particulate fraction upon RIPC induction and that the protection conferred by RIPC can be inhibited with the PKC inhibitor chelerythrine[11][12] Similarly, in models of local PostC, phosphorylation and activation of PKCε has been shown to be induced and PKCε inhibition attenuated the beneficial effects of these regimens.[13][14] A recent study showed that blocking Hsp90 function with geldanamycin inhibits PostC protection and PKCε translocation.[15] Additional studies are required to investigate a role for PKCε in remote PostC and PerC, as this has not been conclusively demonstrated.

References

  1. 1 2 Vinten-Johansen, J; Shi, W (NaN). "Perconditioning and postconditioning: current knowledge, knowledge gaps, barriers to adoption, and future directions.". Journal of cardiovascular pharmacology and therapeutics. 16 (3-4): 260–6. doi:10.1177/1074248411415270. PMID 21821526. Check date values in: |date= (help)
  2. Murry, CE; Jennings, RB; Reimer, KA (November 1986). "Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium.". Circulation. 74 (5): 1124–36. doi:10.1161/01.cir.74.5.1124. PMID 3769170.
  3. Hausenloy, DJ; Yellon, DM (15 February 2004). "New directions for protecting the heart against ischaemia-reperfusion injury: targeting the Reperfusion Injury Salvage Kinase (RISK)-pathway.". Cardiovascular research. 61 (3): 448–60. doi:10.1016/j.cardiores.2003.09.024. PMID 14962476.
  4. Kuzuya, T; Hoshida, S; Yamashita, N; Fuji, H; Oe, H; Hori, M; Kamada, T; Tada, M (June 1993). "Delayed effects of sublethal ischemia on the acquisition of tolerance to ischemia.". Circulation Research. 72 (6): 1293–9. doi:10.1161/01.res.72.6.1293. PMID 8495557.
  5. Marber, MS; Latchman, DS; Walker, JM; Yellon, DM (September 1993). "Cardiac stress protein elevation 24 hours after brief ischemia or heat stress is associated with resistance to myocardial infarction.". Circulation. 88 (3): 1264–72. doi:10.1161/01.cir.88.3.1264. PMID 8353888.
  6. Bolli, R (24 November 2000). "The late phase of preconditioning.". Circulation Research. 87 (11): 972–83. doi:10.1161/01.res.87.11.972. PMID 11090541.
  7. Bolli, R; Li, QH; Tang, XL; Guo, Y; Xuan, YT; Rokosh, G; Dawn, B (December 2007). "The late phase of preconditioning and its natural clinical application--gene therapy.". Heart failure reviews. 12 (3-4): 189–99. doi:10.1007/s10741-007-9031-4. PMC 3652384Freely accessible. PMID 17541820.
  8. Przyklenk, K; Bauer, B; Ovize, M; Kloner, RA; Whittaker, P (March 1993). "Regional ischemic 'preconditioning' protects remote virgin myocardium from subsequent sustained coronary occlusion.". Circulation. 87 (3): 893–9. doi:10.1161/01.cir.87.3.893. PMID 7680290.
  9. Zhao, ZQ; Corvera, JS; Halkos, ME; Kerendi, F; Wang, NP; Guyton, RA; Vinten-Johansen, J (August 2003). "Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning.". American Journal of Physiology. Heart and Circulatory Physiology. 285 (2): H579–88. doi:10.1152/ajpheart.01064.2002. PMID 12860564.
  10. Kerendi, F; Kin, H; Halkos, ME; Jiang, R; Zatta, AJ; Zhao, ZQ; Guyton, RA; Vinten-Johansen, J (September 2005). "Remote postconditioning. Brief renal ischemia and reperfusion applied before coronary artery reperfusion reduces myocardial infarct size via endogenous activation of adenosine receptors.". Basic research in cardiology. 100 (5): 404–12. doi:10.1007/s00395-005-0539-2. PMID 15965583.
  11. Wolfrum, S; Schneider, K; Heidbreder, M; Nienstedt, J; Dominiak, P; Dendorfer, A (15 August 2002). "Remote preconditioning protects the heart by activating myocardial PKCepsilon-isoform.". Cardiovascular research. 55 (3): 583–9. doi:10.1016/s0008-6363(02)00408-x. PMID 12160956.
  12. Weinbrenner, C; Nelles, M; Herzog, N; Sárváry, L; Strasser, RH (15 August 2002). "Remote preconditioning by infrarenal occlusion of the aorta protects the heart from infarction: a newly identified non-neuronal but PKC-dependent pathway.". Cardiovascular research. 55 (3): 590–601. doi:10.1016/s0008-6363(02)00446-7. PMID 12160957.
  13. Zatta, AJ; Kin, H; Lee, G; Wang, N; Jiang, R; Lust, R; Reeves, JG; Mykytenko, J; Guyton, RA; Zhao, ZQ; Vinten-Johansen, J (1 May 2006). "Infarct-sparing effect of myocardial postconditioning is dependent on protein kinase C signalling.". Cardiovascular research. 70 (2): 315–24. doi:10.1016/j.cardiores.2005.11.030. PMID 16443207.
  14. Philipp, S; Yang, XM; Cui, L; Davis, AM; Downey, JM; Cohen, MV (1 May 2006). "Postconditioning protects rabbit hearts through a protein kinase C-adenosine A2b receptor cascade.". Cardiovascular research. 70 (2): 308–14. doi:10.1016/j.cardiores.2006.02.014. PMID 16545350.
  15. Zhong, GQ; Tu, RH; Zeng, ZY; Li, QJ; He, Y; Li, S; He, Y; Xiao, F (15 June 2014). "Novel functional role of heat shock protein 90 in protein kinase C-mediated ischemic postconditioning.". The Journal of surgical research. 189 (2): 198–206. doi:10.1016/j.jss.2014.01.038. PMID 24742623.
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