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

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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.

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Authors and Affiliations

  1. Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Heart and Vascular Institute, Detroit, Michigan, 48202

    Victor G. Sharov M.D., Ph.D., Anastassia V. Todor M.D., Makoto Imai M.D. & Hani N. Sabbah Ph.D. (Director)

  2. Cardiovascular Research, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI, 48202

    Hani N. Sabbah Ph.D. (Director)

Authors
  1. Victor G. Sharov M.D., Ph.D.
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  2. Anastassia V. Todor M.D.
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  3. Makoto Imai M.D.
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  4. Hani N. Sabbah Ph.D.
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Corresponding author

Correspondence to Hani N. Sabbah Ph.D..

Additional information

This study was supported by a grant from the National Heart, Lung, and Blood Institute PO1 HL074237-01.

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Sharov, V.G., Todor, A.V., Imai, M. et al. Inhibition of Mitochondrial Permeability Transition Pores by Cyclosporine A Improves Cytochrome c Oxidase Function and Increases Rate of ATP Synthesis in Failing Cardiomyocytes. Heart Fail Rev 10, 305–310 (2005). https://doi.org/10.1007/s10741-005-7545-1

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  • DOI: https://doi.org/10.1007/s10741-005-7545-1

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