Heart Failure Reviews

, Volume 10, Issue 4, pp 305–310

Inhibition of Mitochondrial Permeability Transition Pores by Cyclosporine A Improves Cytochrome c Oxidase Function and Increases Rate of ATP Synthesis in Failing Cardiomyocytes

  • Victor G. Sharov
  • Anastassia V. Todor
  • Makoto Imai
  • Hani N. Sabbah
Basic Research Contributions

DOI: 10.1007/s10741-005-7545-1

Cite this article as:
Sharov, V.G., Todor, A.V., Imai, M. et al. Heart Fail Rev (2005) 10: 305. doi:10.1007/s10741-005-7545-1

Abstract

Background: We previously showed that mitochondrial respiratory function is abnormal in dogs with chronic heart failure (HF). Mitochondrial permeability transition pores (MPTP) can affect mitochondrial inner membrane potential (Δ < eqid1 > m) and mitochondrial function in normal cardiomyocytes. The potential impact of MPTP on Δ < eqid2 > m and mitochondrial respiratory function in HF has not yet been determined. We tested the hypothesis that cyclosporine A, a potent blocker of the MPTP, can improve mitochondrial function in HF. Methods: Cardiomyocytes were isolated from the left ventricular myocardium of 7 dogs with HF produced by intracoronary microembolizations and from 7 normal dogs. Cardiomyocytes were treated for 24 hours with cyclosporine A. Δ < eqid3 > m, cytochrome c oxidase protein expression, mitochondrial cytochrome c oxidase-dependent respiration (CDOR) and ATP synthesis were measured. Results: Δ < eqid4 > m, protein expression of cytochrome c oxidase, CDOR and the rate of ATP synthesis were decreased in HF compared to normal controls. Inhibition of MPTP in failing cardiomyocytes with low dose of cyclosporine A (0.2 μM) increased Δ < eqid5 > m, preserved expression of cytochrome c oxidase, improved CDOR and the rate of ATP synthesis. Conclusion: MPTP opening contributes to the loss of mitochondrial function observed in the failing heart. Inhibition of MPTP opening represents a potential therapeutic target for the treatment of HF.

Key Words

heart failure mitochondral permeability transition pore mitochondrial respiration ATP cytochrome c oxidase 

Copyright information

© Springer Science + Business Media, LLC 2006

Authors and Affiliations

  • Victor G. Sharov
    • 1
  • Anastassia V. Todor
    • 1
  • Makoto Imai
    • 1
  • Hani N. Sabbah
    • 1
    • 2
  1. 1.Department of Medicine, Division of Cardiovascular MedicineHenry Ford Heart and Vascular InstituteDetroit
  2. 2.Cardiovascular ResearchHenry Ford HospitalDetroit

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