Inhibition of mitochondrial permeability transition pores by cyclosporine A improves cytochrome C oxidase function and increases rate of ATP synthesis in failing cardiomyocytes.
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 (DeltaPsim) and mitochondrial function in normal cardiomyocytes. The potential impact of MPTP on DeltaPsim 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. DeltaPsim, cytochrome c oxidase protein expression, mitochondrial cytochrome c oxidase-dependent respiration (CDOR) and ATP synthesis were measured.


RESULTS
DeltaPsim, 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 microM) increased DeltaPsim, preserved expression of cytochrome c oxidase, improved CDOR and the rate of ATP synthesis.


CONCLUSIONS
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.
Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Heart and Vascular Institute, Detroit, Michigan 48202, USA.
Victor G
VG
Sharov
Anastassia V
AV
Todor
Makoto
M
Imai
Hani N
HN
Sabbah
D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000818:Animals; D019069:Cell Respiration / Q000187:drug effects; D002908:Chronic Disease; D016572:Cyclosporine / Q000494:pharmacology*; D004195:Disease Models, Animal; D004285:Dogs; D003576:Electron Transport Complex IV / Q000096:biosynthesis / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D008564:Membrane Potentials / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D000083162:Mitochondrial Permeability Transition Pore; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000378:metabolism
D004791:Enzyme Inhibitors; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D016572:Cyclosporine; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV