Mitochondrial Pathways, Permeability Transition Pore, and Redox Signaling in Cardioprotection: Therapeutic Implications

Abstract

Reperfusion therapy is the indispensable treatment of acute myocardial infarction (AMI) and must be applied as soon as possible to attenuate the ischemic insult. However, reperfusion is responsible for additional myocardial damage likely involving opening of the mitochondrial permeability transition pore (mPTP). A great part of reperfusion injury occurs during the first minute of reperfusion. The prolonged opening of mPTP is considered one of the endpoints of the cascade to myocardial damage, causing loss of cardiomyocyte function and viability. Opening of mPTP and the consequent oxidative stress due to reactive oxygen and nitrogen species (ROS/RNS) are considered among the major mechanisms of mitochondrial and myocardial dysfunction. Kinases and mitochondrial components constitute an intricate network of signaling molecules and mitochondrial proteins, which interact in response to stressors. Cardioprotective pathways are activated by stimuli such as preconditioning and postconditioning (PostC), obtained with brief intermittent ischemia or with pharmacological agents, which drastically reduce the lethal ischemia/reperfusion injury. The protective pathways converging on mitochondria may preserve their function. Protection involves kinases, adenosine triphosphate-dependent potassium channels, ROS signaling, and the mPTP modulation. Some clinical studies using ischemic PostC during angioplasty support its protective effects, and an interesting alternative is pharmacological PostC. In fact, the mPTP desensitizer, cyclosporine A, has been shown to induce appreciable protections in AMI patients. Several factors and comorbidities that might interfere with cardioprotective signaling are considered. Hence, treatments adapted to the characteristics of the patient (i.e., phenotype oriented) might be feasible in the future. Antioxid. Redox Signal. 00, 000-000.

Cardioprotective effect of preconditioning is more efficient than postconditioning in rats submitted to cardiac ischemia and reperfusion

“…The increase in PKG activity stimulates opening of mKATP, decreasing mitochondrial Ca 2+ overload, ROS production and prolonged opening of MPTP to maintain ATP production [29][30][31][32] . As well as its application in the myocardium, ischemic preconditioning can also be induced by brief interruptions of blood flow to other organs, particularly skeletal muscle.…”

Acidic infusion in early reperfusion affects the activity of antioxidant enzymes in postischemic isolated rat heart

“…It is well known that ischemia and reperfusion (I/R) in the heart induce extensive tissue damage and that a substantial part of myocardial cell death initiated by ischemia occurs at the time of reperfusion [1][2][3][4][5][6][7][8][9][10][11][12][13]. I/R injury can be thus prevented by interventions applied at the time of reflow, that is postconditioning (PostC), which is obtained with brief intermittent ischemia or with pharmacological agents at beginning of reperfusion [4,5,8,12].…”

“…I/R injury can be thus prevented by interventions applied at the time of reflow, that is postconditioning (PostC), which is obtained with brief intermittent ischemia or with pharmacological agents at beginning of reperfusion [4,5,8,12]. As such, ischemic and pharmacological PostC clinical application has been rapid for both STEMI (ST-elevation) patients undergoing coronary reperfusion and for patients undergoing on pump cardiac surgery [3][4][5].…”

“…Ischemia will cause tissue acidification which initially protects against tissue damage, but prolonged acidosis associated with limited nutrient level will eventually cease ATP generation [1][2][3][4][5]8,9,. Nevertheless, a few minutes acidic perfusion (AP) immediately after release of a prolonged coronary occlusion mimics infarct reduction seen with PostC [1][2][3][4]15].…”

Overexpression of the muscle-specific protein, melusin, protects from cardiac ischemia/reperfusion injury

“…In fact, in PreC two temporary distinct protective windows have been described: a first one, which provides protection against myocardial infarction within 2-3 h after preconditioning stimuli, and a second window of protection, occurring at 24-72 h after PreC stimuli, which is characterized by a unique gene expression profile, including HSPs induction [7,47]. The introduction of postconditioning (PostC) as an intervention which can be applied at the time of myocardial reperfusion, has redirected the attention to the early phase of reperfusion as a target for cardioprotection [40,48,50,66,71]. Studying the signaling moieties implicated in PostC versus PreC revealed a common cardioprotective pathway, including, among others, protein kinases such as AKT, ERK1/2 and GSK3β.…”