Postconditioning Inhibits Mitochondrial Permeability Transition

Abstract

Background-Brief periods of ischemia performed just at the time of reperfusion can reduce infarct size, a phenomenon called "postconditioning." After reflow, opening of the mitochondrial permeability transition pore (mPTP) has been involved in lethal reperfusion injury. We hypothesized that postconditioning may modulate mPTP opening. Methods and Results-Anesthetized open-chest rabbits underwent 30 minutes of ischemia and 4 hours of reperfusion.Control hearts underwent no additional intervention. Postconditioning consisted of 4 episodes of 1 minute of coronary occlusion and 1 minute of reperfusion performed after 1 minute of reflow after the prolonged ischemia. Preconditioning consisted of 5 minutes of ischemia and 5 minutes of reperfusion before the 30-minute ischemia. An additional group of rabbits received 5 mg/kg IV of NIM811, a specific inhibitor of the mPTP, 1 minute before reperfusion. Infarct size was assessed by triphenyltetrazolium staining. Mitochondria were isolated from the risk region myocardium, and Ca 2ϩ -induced mPTP opening was assessed by use of a potentiometric method. Postconditioning, preconditioning, and NIM811 significantly limited infarct size, which averaged 29Ϯ4%, 18Ϯ4%, and 20Ϯ4% of the risk region, respectively, versus 61Ϯ6% in controls (PՅ0.001 versus control). The Ca 2ϩ load required to open the mPTP averaged 41Ϯ4, 47Ϯ5, and 67Ϯ9 mol/L CaCl 2 per mg of mitochondrial proteins in postconditioning, preconditioning, and NIM811, respectively, significantly higher than the value of 16Ϯ4 mol/L per mg in controls (PՅ0.05). Conclusions-Postconditioning

Role of Erk1/2, p70s6K, and eNOS in isofluraneinduced cardioprotection during early reperfusionin vivo

“…24 It has become increasing clear that prevention of mPTP opening plays a critical role as an end-effector in myocardial protection against ischemia-reperfusion injury. [25][26][27][28][29] Whether isoflurane inhibits mPTP by attenuating glycogen synthase kinase-3β activity through Erk1/2-p70s6K signaling is presently unknown. This hypothesis is being actively investigated by our laboratory, and certainly appears to be very plausible based on recent findings indicating that desflurane-induced preconditioning is mediated by inhibition of mitochondrial permeability transition.…”

Mild hypothermia reduces per-ischemic reactive oxygen species production and preserves mitochondrial respiratory complexes

“…This has been ubiquitously observed in multiple ischemic insult models such as 5 regional 4 or global ischemia and cardiac arrest 2, 3 . Mitochondrial dysfunction has been 6 mostly investigated during the post-ischemic reperfusion phase 4,5 . Targeting mitochondria is 7 then often considered as a relevant approach to prevent reperfusion injury through, e.g.,…”

“…, opening of the mitochondrial permeability transition pore (mPTP) 4 and cytochrome c 4 release 1, 2 . This has been ubiquitously observed in multiple ischemic insult models such as 5 regional 4 or global ischemia and cardiac arrest 2, 3 .…”

“…direct inhibition of mPTP after myocardial infarction 4 . However, electron microscopy studies 9 have clearly showed that mitochondrial injuries start during the ischemic phase 3,6 .…”

Postconditioning against ischaemia-reperfusion injury: ready for wide application in patients?

“…15,16 Argaud et al were the first to link IPOC with the inhibition of mPTP opening, by demonstrating increased calcium retention in mitochondria isolated from postconditioned in vivo rabbit hearts compared with control hearts. 17 Furthermore, mice lacking mitochondrial cyclophilin D, a presumed regulatory component of the mPTP, are resistant to cardioprotective effects of both IPC and IPOC, 18 confirming the regulatory role of mPTP. More recently, it has been shown that administration of a single bolus of cyclosporin A, an inhibitor of mPTP opening, at the time of reperfusion was associated with a smaller infarct size in patients with AMI.…”