Skip to main content
SpringerLink
Log in
Book cover

Myocardial Ischemia and Preconditioning pp 189–204Cite as

Cardioprotection by Mitochondrial KATP Channel in Both Early and Late Preconditioning

  • Chapter

  • 103 Accesses

Part of the book series: Progress in Experimental Cardiology ((PREC,volume 6))

Summary

Activation of the mitochondrial KATP channel (mitoKATP) has been shown to confer an early and late phase of cardioprotection against ischemic injury via protein kinase C (PKC) signaling pathways. However, the exact relationship between PKC or its isoforms and mitoKATP channels has not yet been clarified in both early and late preconditioning (PC). The hypothesis of this study is that the translocation of PKC to mitochondria is important for early cardiac protection elicited by mitoKATP channels. PKC was down-regulated by treatment of PMA (4μg/kg) for 24-hours prior to subsequent experiments. Langendorff-perfused rat hearts were subjected to 40-min of ischemia followed by 30-min reperfusion. In late PC, nitric oxide was hypothesized to be trigger for the opening of mitoKATP channels to enable the heart to protect itself against ischemic damage. This was tested in iNOS knockout mouse hearts. Effects of PKC down-regulation or blockade of PKC activity by chelerythrine on the activation of mitoKATP channel and other interventions on hemodynamic, biochemical and pathological changes were assessed. Subcellular distribution of PKC isoforms by immunocy-tochemistry demonstrates that immunostaining of PKC-δ was observed in the mitochondria after diazoxide (DE, 80μmol/L) pretreatment, PKC-ε was translocated to intercalated disc and PKC-β1 was translocated to the nucleus. In DE treated hearts, a significant improvement in cardiac function and attenuation of cell injury was observed. In the PKC down-regulated hearts or hearts pretreated with chelerythrine, the protection was abolished because mitoKATP channels could not be activated by DE. These data suggest that PKC activation is required for the opening of mitoKATP channels in the protection against ischemia and this effect is linked with isoform specific translocation of δ to mitochondria. NO is an important trigger for the opening of mitoKATP channels after 24 hours of initial preconditioning stimulus. DE was found to be totally ineffective in iNOS knockout mice. DE activated NF-kB via PKC signaling pathway and that lead to NOS up-regulation for further activation of the mitoKATP after 24 hours upon ischemic stimulus.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Wang Y, Hirai K, Ashraf M. 1999. Activation of mitochondrial ATP-sensitive K+ channel for cardiac protection against ischemic injury is dependent on protein kinase C activity. Circ Res 85:731–741.

    Article  PubMed  CAS  Google Scholar 

  2. Sato T, O’Rourke B, Marban E. 1998. Modulation of mitochondrial ATP-dependent K+ channels by protein kinase C. Circ Res 83:110–114.

    Article  PubMed  CAS  Google Scholar 

  3. Hu K, Duan D, Li GR, Nattel S. 1996. Protein kinase C activates ATP-sensitive K+ current in human and rabbit ventricular myocytes. Circ Res 78:492–498.

    Article  PubMed  CAS  Google Scholar 

  4. Takashi E, Wang Y, Ashraf M. 1999. Activation of mitochondrial KATP channel elicits late preconditioning against myocardial infarction via protein kinase C signaling pathway. Circ Res 85:1146–1153.

    Article  PubMed  CAS  Google Scholar 

  5. Henrich CJ, Simpson PC. 1988. Differential acute and chronic response of Protein kinase C in cultured neonatal rat heart myocytes to α1-adrenergic and phorbol ester stimulation. J Mol Cell Cardiol 20:1081–1085.

    Article  PubMed  CAS  Google Scholar 

  6. Wang Y, Takashi E, Xu M, Ayub A, Ashraf M. 2001. Downregulation of protein kinase C inhibits activation of mitochondrial KATP channels by diazoxide. Cirulation 104:85–90.

    Article  CAS  Google Scholar 

  7. Dayton PG, Pruitt AW, Faraj BA, Israili ZH. 1975. Metabolism and disposition of diazoxide: a mini-review. Drug Metab Dispos 3:226–229.

    PubMed  CAS  Google Scholar 

  8. Ockaili R, Emani VR, Okubo S, Brown M, Krottapalli K, Kukreja RC. 1999. Opening of mitochondrial KATP channel induces early and delayed cardioprotective effect: role of nitric oxide. Am J Physiol 277(6):H2425–2434.

    PubMed  CAS  Google Scholar 

  9. Wang Y, Ashraf M. 1999. Role of protein kinase C in mitochondrial KATP channel-mediated protection against Ca2+ overload injury in rat myocardium. Circ Res 84:1156–1165.

    Article  PubMed  CAS  Google Scholar 

  10. Wang Y, Ashraf M. 1998. Activation of α1-adrenergic receptor during Ca2+ pre-conditioning elicits strong protection against Ca2+ overload injury via protein kinase C signaling pathway. J Mol Cell Cardiol 30:2423–2435.

    Article  PubMed  CAS  Google Scholar 

  11. Wang Y, Kudo M, Xu M, Ayub A. Ashraf M. 2001. Mitochondrial KATP channel as an end effector of cardioprotection during late preconditioning: Triggering role of nitric oxide. J Mol Cell Cardiol 33:2037–2047.

    Article  PubMed  CAS  Google Scholar 

  12. Baldwin AS. 1996. The NF-κB and IκB proteins: New discoveries and insights. Annu Rev Immunol 14:649–681.

    Article  PubMed  CAS  Google Scholar 

  13. Mitchell MB, Meng X, Ao L, Brown JM, Harken AH, Banerjee A. 1995. Preconditioning of isolated rat heart is mediated by protein kinase C. Circ Res 76:73–81.

    Article  PubMed  CAS  Google Scholar 

  14. Young S, Parker PJ, Ullrich A, Stabel S. 1987. Down-regulation of protein kinase C is due to an increased rate of degradation. Biochem J 244:775–779.

    PubMed  CAS  Google Scholar 

  15. Junco M, Webster C, Crawford C, Bosca L, Parker PJ. 1994. Protein kinase C V3 domain mutants with differential sensitivities to m-calpain are not resistant to phorbol-ester-induced down-regulation. Eur J Biochem 223:259–263.

    Article  PubMed  CAS  Google Scholar 

  16. Takeishi Y, Jalili T, Ball NA, Walsh RA. 1999. Responses of cardiac protein kinase C isoforms to distinct pathological stimuli are differentially regulated. Circ Res 85:264–271.

    Article  PubMed  CAS  Google Scholar 

  17. Mochly-Rosen D, Wu G, Hahn H, Osinska H, Liron T, Lorenz JN, Yatani A, Robbins J, Dorn GW 2nd. 2000. Cardiotropic effects of protein kinase C ε. Analysis by in vivo modulation of PKC ε translocation. Circ Res 86:1173–1179.

    Article  PubMed  CAS  Google Scholar 

  18. Borner C, Ueffing M, Jaken S, Parker PJ, Weinstein IB. 1995. Two closely related isoforms of protein kinase C produce reciprocal effects on the growth of rat fibroblasts. J Biol Chem 270:78–86.

    Article  PubMed  CAS  Google Scholar 

  19. Kawamura S, Yoshita K, Miura T, Mizukami Y, Matsuzaki M. 1998. Ischemic preconditioning translocation PKC-δ and -ε, which mediate functional protection in isolated rat heart. Am J Physiol 275:H2266–H2271.

    PubMed  CAS  Google Scholar 

  20. Liu GS, Cohen MV, Mochly-Rosen D, Downey JM. 1999. Protein kinase C-ε is responsible for the protection of preconditioning in rabbits cardiomyocytes. J Mol Cell Cardiol 31 (10): 1937–1948.

    Article  PubMed  CAS  Google Scholar 

  21. Dorn GW II, Souroujan 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 cause ε protein kinase C translocation. Proc Natl Acad Sei 96:12798–12803.

    Article  CAS  Google Scholar 

  22. Light PE, Bladen C, Winkfein RJ, Walsh MP, French RJ. 2000. Molecular basis of protein kinase C-induced activation of ATP-sensitive potassium channels. Proc Natl Acad Sei 97:9058–9063.

    Article  CAS  Google Scholar 

  23. Parratt JR, Kane KA. 1994. KATP channels in ischemic preconditioning. Cardiovasc Res 28(6): 783–787.

    Article  PubMed  CAS  Google Scholar 

  24. Wilson S, Song W, Karoly K, Ravingerova T, Vegh A, Papp J, Tomisawa S, Parratt JR, Pyne NJ. 1996. Delayed cardioprotection is associated with the sub-cellular relocalisation of ventricular protein kinase C epsilon, but not p42/44MAPK. Mol Cell Biochem 160:225-230.

    Article  PubMed  Google Scholar 

  25. Araki M, Tanaka M, Hasegawa K, Yokota R, Maeda T, Ishikawa M, Yabuuchi Y, Sasayama S. 2000. Nitric oxide inhibition improved myocardial metabolism independent of tissue perfusion during ischemia but not during reperfusion. J Moll Cell Cardiol 32:375–384.

    Article  CAS  Google Scholar 

  26. Cameron JS, Baghdady R.1994. Role of ATP sensitive potassium channels in long term adaptation to metabolic stress. Cardiovasc Res 28:788–796.

    Article  PubMed  CAS  Google Scholar 

  27. Gross GJ, Auchampach JA. 1992. Blockade of ATP-sensitive potassium channels prevents myocardial preconditioning in dogs. Circ Res 70:223–233

    Article  PubMed  CAS  Google Scholar 

  28. Sasaki N, Sato T, Ohler A, O’Rourke B, Marban E. 2000. Activation of Mitochondrial ATP-dependent potassium channels by nitric oxide. Circulation 101:439–445.

    Article  PubMed  CAS  Google Scholar 

  29. 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.

    Article  PubMed  CAS  Google Scholar 

  30. Chen CC, Wang JK, Lin SB. 1998. Antisense oligonucleotides targeting protein kinase C-α, -βI, or -δ but not -η inhibit lipopolysaccharide-induced nitric oxide synthase expression in RAW 264.7 macrophages: involvement of a nuclear factor kappa B-dependent mechanism. J Immunol 161:6206–6214.

    PubMed  CAS  Google Scholar 

  31. Xu M, Wang Y, Ayub A, Ashraf M. 2001. Mitochondrial KATP channel activation reduces anoxic injury by restoring mitochondrial membrane potential. Am J Physiol Heart Circ Physiol 281:H1295–H1303.

    PubMed  CAS  Google Scholar 

  32. Fryer RM, Eells JT, Hsu AK, Henry MM, Gross GJ. 2000. Ischemic preconditioning in rats: role of mitochondrial KATP channel in preservation of mitochondrial function. Am J Physiol 278:H305–H312.

    CAS  Google Scholar 

  33. Xuan YT, Tang XL, Banerjee S, Takano H, Li RC, Han H, Qiu Y, Li JJ, Bolli R. 1999. Nuclear Factor-κB Plays an Essential Role in the Late Phase of Ischemic Preconditioning in Conscious Rabbits. Circulation Research 84:1095–1109

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, 231 Albert Sabin Way, 45267-0529, Cincinnati, Ohio, USA

    Yigang Wang, Meifeng Xu, Mitsuhiro Kudo, Ahmar Ayub & Muhammad Ashraf Ph.D.

Authors
  1. Yigang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Meifeng Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mitsuhiro Kudo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ahmar Ayub
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Muhammad Ashraf Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Muhammad Ashraf Ph.D. .

Editor information

Editors and Affiliations

  1. Institute of Cardiovascular Sciences St. Boniface General Hospital Research Centre Faculty of Medicine, University of Manitoba, Winnipeg, Canada

    Naranjan S. Dhalla PhD, MD (Hon), DSc (Hon) (Distinguished Professor and Director) & Anton Lukas PhD (Associate Professor) (Distinguished Professor and Director) &  (Associate Professor)

  2. Aoto Hospital, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan

    Nobuakira Takeda MD, PhD (Associate Professor) (Associate Professor)

  3. Dept. of Pharmaceutical Sciences & Drug Research, Punjabi University, Patiala, India

    Manjeet Singh PhD (Professor & Head) (Professor & Head)

Rights and permissions

Reprints and permissions

Copyright information

© 2003 Springer Science+Business Media New York

About this chapter

Cite this chapter

Wang, Y., Xu, M., Kudo, M., Ayub, A., Ashraf, M. (2003). Cardioprotection by Mitochondrial KATP Channel in Both Early and Late Preconditioning. In: Dhalla, N.S., Takeda, N., Singh, M., Lukas, A. (eds) Myocardial Ischemia and Preconditioning. Progress in Experimental Cardiology, vol 6. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0355-2_14

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-0355-2_14

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-5036-1

  • Online ISBN: 978-1-4615-0355-2

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation