scholarly journals Preconditioning or Postconditioning with 8-Br-cAMP-AM Protects the Heart against Regional Ischemia and Reperfusion: A Role for Mitochondrial Permeability Transition

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1223
Author(s):  
Igor Khaliulin ◽  
Raimondo Ascione ◽  
Leonid N. Maslov ◽  
Haitham Amal ◽  
M. Saadeh Suleiman
Keyword(s):  
Infarct Size ◽  
Ventricular Arrhythmias ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Protective Mechanism ◽  
Hexokinase Ii ◽  
Perfused Heart ◽  
Mitochondrial Permeability ◽  
Ischaemia Reperfusion

The cAMP analogue 8-Br-cAMP-AM (8-Br) confers marked protection against global ischaemia/reperfusion of isolated perfused heart. We tested the hypothesis that 8-Br is also protective under clinically relevant conditions (regional ischaemia) when applied either before ischemia or at the beginning of reperfusion, and this effect is associated with the mitochondrial permeability transition pore (MPTP). 8-Br (10 μM) was administered to Langendorff-perfused rat hearts for 5 min either before or at the end of 30 min regional ischaemia. Ca2+-induced mitochondria swelling (a measure of MPTP opening) and binding of hexokinase II (HKII) to mitochondria were assessed following the drug treatment at preischaemia. Haemodynamic function and ventricular arrhythmias were monitored during ischaemia and 2 h reperfusion. Infarct size was evaluated at the end of reperfusion. 8-Br administered before ischaemia attenuated ventricular arrhythmias, improved haemodynamic function, and reduced infarct size during ischaemia/reperfusion. Application of 8-Br at the end of ischaemia protected the heart during reperfusion. 8-Br promoted binding of HKII to the mitochondria and reduced Ca2+-induced mitochondria swelling. Thus, 8-Br protects the heart when administered before regional ischaemia or at the beginning of reperfusion. This effect is associated with inhibition of MPTP via binding of HKII to mitochondria, which may underlie the protective mechanism.

scholarly journals Blockade of the Mitochondrial Permeability Transition Pore Diminishes Infarct Size in the Rat after Transient Middle Cerebral Artery Occlusion

1999 ◽  
Vol 19 (7) ◽  
pp. 736-741 ◽  
Author(s):  
Shohei Matsumoto ◽  
Hans Friberg ◽  
Michel Ferrand-Drake ◽  
Tadeusz Wieloch
Keyword(s):  
Infarct Size ◽  
Cyclosporin A ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Artery Occlusion ◽  
Mitochondrial Permeability ◽  
Transient Focal Ischemia ◽  
Cerebral Artery Occlusion

The mitochondrial permeability transition pore is an inducer of cell death. During the reperfusion phase after cerebral ischemia, calcium accumulates in mitochondria, and a burst of free radical formation occurs, conditions that favor the activation of the mitochondrial permeability transition pore. Here the authors demonstrate that a blocker of the mitochondrial permeability transition pore, the nonimmunosuppressive cyclosporin A analogue N-methyl-Val-4-cyclosporin A (10 mg/kg intraperitoneally), administered during reperfusion and at 24 hours of reperfusion, diminishes infarct size in a rat model of transient focal ischemia of 2 hours' duration. The mitochondrial permeability transition pore may be an important target for drugs against stroke.

Altered FoF1 ATP synthase and susceptibility to mitochondrial permeability transition pore during ischaemia and reperfusion in aging cardiomyocytes

2015 ◽  
Vol 113 (03) ◽  
pp. 441-451 ◽  
Author(s):  
Celia Fernandez-Sanz ◽  
José Castellano ◽  
Elisabet Miro-Casas ◽  
Estefanía Nuñez ◽  
Javier Inserte ◽  
...  
Keyword(s):  
Atp Synthase ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Calcium Overload ◽  
Mitochondrial Permeability ◽  
Mptp Opening ◽  
Ischaemia Reperfusion ◽  
Fof1 Atp Synthase

SummaryAging is a major determinant of the incidence and severity of ischaemic heart disease. Preclinical information suggests the existence of intrinsic cellular alterations that contribute to ischaemic susceptibility in senescent myocardium, by mechanisms not well established. We investigated the role of altered mitochondrial function in the adverse effect of aging. Isolated perfused hearts from old mice (> 20 months) displayed increased ischaemia-reperfusion injury as compared to hearts from adult mice (6 months) despite delayed onset of ischaemic rigor contracture. In cardiomyocytes from aging hearts there was a more rapid decline of mitochondrial membrane potential (ΔΨm) as compared to young ones, but ischaemic rigor shortening was also delayed. Transient recovery of ΔΨm observed during ischaemia, secondary to the reversal of mitochondrial FoF1 ATP synthase to ATPase mode, was markedly reduced in aging cardiomyocytes. Proteomic analysis demonstrated increased oxidation of different subunits of ATP synthase. Altered bionergetics in aging cells was associated with reduced mitochondrial calcium uptake and more severe cytosolic calcium overload during ischaemia-reperfusion. Despite attenuated ROS burst and mitochondrial calcium overload, mitochondrial permeability transition pore (mPTP) opening and cell death was increased in reperfused aged cells. In vitro studies demonstrated a significantly reduced calcium retention capacity in interfibrillar mitochondria from aging hearts. Our results identify altered FoF1 ATP synthase and increased sensitivity of mitochondria to undergo mPTP opening as important determinants of the reduced tolerance to ischaemia-reperfusion in aging hearts. Because ATP synthase has been proposed to conform mPTP, it is tempting to hypothesise that oxidation of ATP synthase underlie both phenomena.

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