Cardioprotective reperfusion strategies differentially affect mitochondria: Studies in an isolated rat heart model of donation after circulatory death (DCD)

Abstract

Donation after circulatory death (DCD) holds great promise for improving cardiac graft availability; however, concerns persist regarding injury following warm ischemia, after donor circulatory arrest, and subsequent reperfusion. Application of preischemic treatments is limited for ethical reasons; thus, cardioprotective strategies applied at graft procurement (reperfusion) are of particular importance in optimizing graft quality. Given the key role of mitochondria in cardiac ischemia-reperfusion injury, we hypothesize that 3 reperfusion strategies-mild hypothermia, mechanical postconditioning, and hypoxia, when briefly applied at reperfusion onset-provoke mitochondrial changes that may underlie their cardioprotective effects. Using an isolated, working rat heart model of DCD, we demonstrate that all 3 strategies improve oxygen-consumption-cardiac-work coupling and increase tissue adenosine triphosphate content, in parallel with increased functional recovery. These reperfusion strategies, however, differentially affect mitochondria; mild hypothermia also increases phosphocreatine content, while mechanical postconditioning stimulates mitochondrial complex I activity and reduces cytochrome c release (marker of mitochondrial damage), whereas hypoxia upregulates the expression of peroxisome proliferator-activated receptor-gamma coactivator (regulator of mitochondrial biogenesis). Characterization of the role of mitochondria in cardioprotective reperfusion strategies should aid in the identification of new, mitochondrial-based therapeutic targets and the development of effective reperfusion strategies that could ultimately facilitate DCD heart transplantation.

Mechanical Postconditioning Promotes Glucose Metabolism and AMPK Activity in Parallel with Improved Post-Ischemic Recovery in an Isolated Rat Heart Model of Donation after Circulatory Death

“…Importantly, MPC can inhibit irreversible opening of the mitochondrial permeability transition pore (mPTP), which is associated with the release of cytochrome c and the collapse of the membrane potential and leads to cell death [43,44]. We have previously reported that MPC-induced cardioprotection is associated with improved mitochondrial function (greater complex I activity and ATP content and less cyt c release) in a similar model, therefore supporting the concept of MPC-induced mitochondrial preservation [45]. Interestingly, evidence exists to support a role for AMPK in the inhibition of mPTP opening [32], which is consistent with a role for AMPK in the cardioprotection observed in HiR MPC hearts.…”

“…An isolated heart model of DCD heart transplantation was used, as previously reported [26,45,47,53,54], with male Wistar rats (Janvier Labs, Le Genest-Saint-Isle, France) of 10 to 11 weeks of age to ensure mature cardiac metabolism [55] and to represent young, adult human DCD donors. Rats were housed under standard conditions at a controlled room temperature with a 12-h light-dark cycle and access to water and food ad libitum.…”

“…To obtain data for cardiac function, a micro-tip pressure catheter (Millar, Houston, TX, USA) placed in the left ventricle was used to continuously measure heart rate (HR), peak systolic pressure, developed pressure (DP), minimum and maximum first derivatives of left ventricular pressure (dP/dt min and dP/dt max). Left ventricular work (LV work) was calculated as previously described [45,47,53,54]: DP × HR.…”

Pre-ischemic Lactate Levels Affect Post-ischemic Recovery in an Isolated Rat Heart Model of Donation After Circulatory Death (DCD)

“…A well-established isolated rat heart model of DCD was used (16,(28)(29)(30)(31). Male Wistar rats (Janvier Labs, Le Genest-Saint-Isle, France) aged 11-12 weeks were used to ensure mature cardiac metabolism (32) and to represent young, adult human DCD donors.…”

Melatonin improves mitochondrial biogenesis through the AMPK/PGC1α pathway to attenuate ischemia/reperfusion-induced myocardial damage

“…Defective mitophagy has been observed in cardiac I/R injury, and is associated with mitochondrial dysfunction in cardiomyocytes and cardiac microvascular endothelial cells [15,16]. Similarly, mitochondrial biogenesis was found to be inhibited in a mouse model of cardiac I/R injury; thus, improving mitochondrial biogenesis is considered to be a promising method of alleviating cardiac I/R injury [17,18]. However, there is not yet an effective drug to promote mitochondrial biogenesis in the heart.…”