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The late phase of preconditioning and its natural clinical application—gene therapy

Heart Failure Reviews volume 12, pages 189–199 (2007)Cite this article

Abstract

There is little doubt that the discovery of ischemic preconditioning (PC) has been one of the fundamental milestones in the field of ischemic biology in the past 20 years. The purpose of this article is to review the pathophysiology and molecular basis of the late phase of myocardial PC. The exploitation of late PC for the development of novel gene therapy strategies aimed at inducing a permanently preconditioned cardiac phenotype (prophylactic cardioprotection) will also be discussed. Deciphering the mechanism of late PC has not only conceptual interest but also a considerable therapeutic implications, since transfer of the genes that underlie late PC would be expected to replicate the salubrious effects of this response of the heart to stress.

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References

  1. Murry CE, Jennings RB, Reimer KA (1986) Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74:1124–1136

    PubMed  CAS  Google Scholar 

  2. Bolli R, Becker L, Gross G, Mentzer R Jr, Balshaw D, Lathrop DA (2004) Myocardial protection at a crossroads: the need for translation into clinical therapy. Circ Res 95:125–134

    PubMed  Article  CAS  Google Scholar 

  3. Bolli R (2000) The late phase of preconditioning. Circ Res 87:972–983

    PubMed  CAS  Google Scholar 

  4. Yellon DM, Downey JM (2003) Preconditioning the myocardium: from cellular physiology to clinical cardiology. Physiol Rev 83:1113–1151

    PubMed  CAS  Google Scholar 

  5. Guo Y, Wu WJ, Zhu XP, Li Q, Tang XL, Bolli R (2001) Exercise-induced late preconditioning is triggered by generation of nitric oxide. J Mol Cell Cardiol 33:A41 (Abstr.)

    Google Scholar 

  6. Kuzuya T, Hoshida S, Yamashita N, Fuji H, Oe H, Hori M, Kamada T, Tada M (1993) Delayed effects of sublethal ischemia on the acquisition of tolerance to ischemia. Circ Res 72:1293–1299

    PubMed  CAS  Google Scholar 

  7. Marber MS, Latchman DS, Walker JM, Yellon DM (1993) Cardiac stress protein elevation 24 hours after brief ischemia or heat stress is associated with resistance to myocardial infarction. Circulation 88:1264–1272

    PubMed  CAS  Google Scholar 

  8. Bolli R, Manchikalapudi S, Tang XL, Takano H, Qiu Y, Guo Y, Zhang Q, Jadoon AK (1997) The protective effect of late preconditioning against myocardial stunning in conscious rabbits is mediated by nitric oxide synthase. Evidence that nitric oxide acts both as a trigger and as a mediator of the late phase of ischemic preconditioning. Circ Res 81:1094–1107

    PubMed  CAS  Google Scholar 

  9. Guo Y, Jones WK, Xuan YT, Tang XL, Bao W, Wu WJ, Han H, Laubach VE, Ping P, Yang Z, Qiu Y, Bolli R (1999) The late phase of ischemic preconditioning is abrogated by targeted disruption of the inducible NO synthase gene. Proc Natl Acad Sci USA 96:11507–11512

    PubMed  Article  CAS  Google Scholar 

  10. Bolli R, Dawn B, Tang XL, Qiu Y, Ping P, Xuan YT, Jones WK, Takano H, Guo Y, Zhang J (1998) The nitric oxide hypothesis of late preconditioning. Basic Res Cardiol 93:325–338

    PubMed  Article  CAS  Google Scholar 

  11. Bolli R (2001) Cardioprotective function of inducible nitric oxide synthase and role of nitric oxide in myocardial ischemia and preconditioning: an overview of a decade of research. J Mol Cell Cardiol 33:1897–1918

    PubMed  Article  CAS  Google Scholar 

  12. Jones SP, Bolli R (2006) The ubiquitous role of nitric oxide in cardioprotection. J Mol Cell Cardiol 40:16–23

    PubMed  Article  CAS  Google Scholar 

  13. Wang Y, Guo Y, Zhang SX, Wu WJ, Wang J, Bao W, Bolli R (2002) Ischemic preconditioning upregulates inducible nitric oxide synthase in cardiac myocyte. J Mol Cell Cardiol 34:5–15

    PubMed  Article  CAS  Google Scholar 

  14. Bolli R, Shinmura K, Tang XL, Kodani E, Xuan YT, Guo Y, Dawn B (2002) Discovery of a new function of cyclooxygenase (COX)-2: COX-2 is a cardioprotective protein that alleviates ischemia/reperfusion injury and mediates the late phase of preconditioning. Cardiovasc Res 55:506–519

    PubMed  Article  CAS  Google Scholar 

  15. Shinmura K, Tang XL, Wang Y, Xuan YT, Liu SQ, Takano H, Bhatnagar A, Bolli R (2000) Cyclooxygenase-2 mediates the cardioprotective effects of the late phase of ischemic preconditioning in conscious rabbits. Proc Natl Acad Sci USA 97:10197–10202

    PubMed  Article  CAS  Google Scholar 

  16. Shinmura K, Bolli R (2005) The risk for myocardial infarction with cyclooxygenase-2 inhibitors. Ann Intern Med 143:615–618

    Google Scholar 

  17. Shinmura K, Xuan YT, Tang XL, Kodani E, Han H, Zhu Y, Bolli R (2002) Inducible nitric oxide synthase modulates cyclooxygenase-2 activity in the heart of conscious rabbits during the late phase of ischemic preconditioning. Circ Res 90:602–608

    PubMed  Article  CAS  Google Scholar 

  18. Xuan YT, Guo Y, Zhu Y, Han H, Langenbach R, Dawn B, Bolli R (2003) Mechanism of cyclooxygenase-2 upregulation in late preconditioning. J Mol Cell Cardiol 35:525–537

    PubMed  Article  CAS  Google Scholar 

  19. Kim SF, Huri DA, Snyder SH (2005) Inducible nitric oxide synthase binds, S-nitrosylates, and activates cyclooxygenase-2. Science 310:1966–1970

    PubMed  Article  CAS  Google Scholar 

  20. Ueda Y, Kitakaze M, Komamura K, Minamino T, Asanuma H, Sato H, Kuzuya T, Takeda H, Hori M (1999) Pravastatin restored the infarct size-limiting effect of ischemic preconditioning blunted by hypercholesterolemia in the rabbit model of myocardial infarction. J Am Coll Cardiol 34:2120–2125

    PubMed  Article  CAS  Google Scholar 

  21. Tang XL, Takano H, Xuan YT, Sato H, Kodani E, Dawn B, Zhu Y, Shirk G, Wu WJ, Bolli R (2005) Hypercholesterolemia abrogates late preconditioning via a tetrahydrobiopterin-dependent mechanism in conscious rabbits. Circulation 112:2149–2156

    PubMed  Article  Google Scholar 

  22. Tang XL, Stein AB, Shirk G, Bolli R (2004) Hypercholesterolemia blunts NO donor-induced late preconditioning against myocardial infarction in conscious rabbits. Basic Res Cardiol 99:395–403

    PubMed  Article  Google Scholar 

  23. Kremastinos DT, Bofilis E, Karavolias GK, Papalois A, Kaklamanis L, Iliodromitis EK (2000) Preconditioning limits myocardial infarct size in hypercholesterolemic rabbits. Atherosclerosis 150:81–89

    PubMed  Article  CAS  Google Scholar 

  24. Tsang A, Hausenloy DJ, Mocanu MM, Carr RD, Yellon DM (2005) Preconditioning the diabetic heart: the importance of Akt phosphorylation. Diabetes 54:2360–2364

    PubMed  Article  CAS  Google Scholar 

  25. Kristiansen SB, Lofgren B, Stottrup NB, Khatir D, Nielsen-Kudsk JE, Nielsen TT, Botker HE, Flyvbjerg A (2004) Ischaemic preconditioning does not protect the heart in obese and lean animal models of type 2 diabetes. Diabetologia 47:1716–1721

    PubMed  Article  CAS  Google Scholar 

  26. del Valle HF, Lascano EC, Negroni JA, Crottogini AJ (2003) Absence of ischemic preconditioning protection in diabetic sheep hearts: role of sarcolemmal KATP channel dysfunction. Mol Cell Biochem 249:21–30

    PubMed  Article  Google Scholar 

  27. Fenton RA, Dickson EW, Meyer TE, Dobson JG Jr (2000) Aging reduces the cardioprotective effect of ischemic preconditioning in the rat heart. J Mol Cell Cardiol 32:1371–1375

    PubMed  Article  CAS  Google Scholar 

  28. Abete P, Ferrara N, Cioppa A, Ferrara P, Bianco S, Calabrese C, Cacciatore F, Longobardi G, Rengo F (1996) Preconditioning does not prevent postischemic dysfunction in aging heart. J Am Coll Cardiol 27:1777–1786

    PubMed  Article  CAS  Google Scholar 

  29. Boengler K, Konietzka I, Buechert A, Heinen Y, Garcia-Dorado D, Heusch G, Schulz R (2006) Loss of ischemic preconditioning’s cardioprotection in aged mouse hearts is associated with reduced gap junctional and mitochondrial levels of connexin 43. Am J Physiol Heart Circ Physiol (in press)

  30. Przyklenk K, Li G, Whittaker P (2001) No loss in the in vivo efficacy of ischemic preconditioning in middle-aged and old rabbits. J Am Coll Cardiol 38:1741–1747

    PubMed  Article  CAS  Google Scholar 

  31. Wu WJ, Xuan YT, Tan W, Zhu X, Zhu Y, Guo Y (2003) The loss of ischemic preconditioning in the senescent heart is associated with impaired upregulation of inducible nitric oxide synthase and cyclooxygenase-2. Circulation 108:IV–187 (Abstr.)

    Google Scholar 

  32. Shinmura K, Nagai M, Tamaki K, Bolli R (2004) Gender and aging do not impair opioid-induced late preconditioning in rats. Basic Res Cardiol 99:46–55

    PubMed  Article  CAS  Google Scholar 

  33. Li Q, Guo Y, Xuan YT, Lowenstein CJ, Stevenson SC, Prabhu SD, Wu WJ, Zhu Y, Bolli R (2003) Gene therapy with inducible nitric oxide synthase protects against myocardial infarction via a cyclooxygenase-2-dependent mechanism. Circ Res 92:741–748

    PubMed  Article  CAS  Google Scholar 

  34. Li Q, Guo Y, Tan W, Stein AB, Dawn B, Wu WJ, Zhu X, Lu X, Xu X, Siddiqui T, Tiwari S, Bolli R (2006) Gene therapy with iNOS provides long-term protection against myocardial infarction without adverse functional consequences. Am J Physiol Heart Circ Physiol 290:H584–H589

    PubMed  Article  CAS  Google Scholar 

  35. Guo Y, Luo C, Dawn B, Tan W, Wu WJ, Hunt G, Zhu X, Li Q (2004) The cardioprotection afforded by iNOS gene therapy is mediated by COX-2 via an NF-kappaB-dependent pathway. Circulation 110:III–29 (Abstr.)

    Google Scholar 

  36. Xuan YT, Tang XL, Banerjee S, Takano H, Li RC, Han H, Qiu Y, Li JJ, Bolli R (1999) Nuclear factor-kappaB plays an essential role in the late phase of ischemic preconditioning in conscious rabbits. Circ Res 84:1095–1109

    PubMed  CAS  Google Scholar 

  37. Appleby SB, Ristimaki A, Neilson K, Narko K, Hla T (1994) Structure of the human cyclo-oxygenase-2 gene. Biochem J 302 (Pt 3):723–727

    PubMed  CAS  Google Scholar 

  38. Dawn B, Xuan YT, Marian M, Flaherty MP, Murphree SS, Smith TL, Bolli R, Jones WK (2001) Cardiac-specific abrogation of NF- kappa B activation in mice by transdominant expression of a mutant I kappa B alpha. J Mol Cell Cardiol 33:161–173

    PubMed  Article  CAS  Google Scholar 

  39. Verma IM, Weitzman MD (2005) Gene therapy: twenty-first century medicine. Annu Rev Biochem 74:711–738

    PubMed  Article  CAS  Google Scholar 

  40. Li Q, Guo Y, Luo C, Tan W, Wu WJ, Xu B, Siddiqui T, Rokosh GD, Bolli R (2004) Long-term protection against myocardial infarction with cyclooxygenase-2 (COX-2) gene therapy via a recombinant adeno-associated viral (rAAV) vector. Circulation 110:III–107 (Abstr.)

    Google Scholar 

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Acknowledgments

This study was supported in part by NIH R01 grants HL-55757, HL-68088, HL-70897, HL-76794, HL-78825, and HL-74351.

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Affiliations

  1. Division of Cardiology, University of Louisville, 550 S. Jackson St., ACB, 3rd floor, Louisville, KY, 40292, USA

    Roberto Bolli, Qian-Hong Li, Xian-Liang Tang, Yiru Guo, Yu-Ting Xuan, Gregg Rokosh & Buddhadeb Dawn

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  1. Roberto Bolli
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  2. Qian-Hong Li
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Correspondence to Roberto Bolli.

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Bolli, R., Li, QH., Tang, XL. et al. The late phase of preconditioning and its natural clinical application—gene therapy. Heart Fail Rev 12, 189–199 (2007). https://doi.org/10.1007/s10741-007-9031-4

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Keywords

  • Nitric oxide synthase
  • Protection
  • Cyclooxygenase-2
  • Late preconditioning