Cardioprotective strategies in myocardial ischemia-reperfusion injury: Implications for improving clinical translation

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  Fig. 1. Mechanisms and inhibition strategies of ischemia-reperfusion injury in cardiomyocytes. During ischemia, the anaerobic respiration induced by hypoxia results in an increase in lactate production and a concomitant decrease in pH. The acidic environment increases the intracellular calcium concentration via the sodium/hydrogen exchanger (NHE) and sodium/calcium exchanger (NCX), while simultaneously inhibiting the opening of the mitochondrial permeability transition pore (MPTP). Meanwhile, the hypoxic environment results in a significant conversion of ATP to AMP in the mitochondria. During reperfusion, a delay in the regeneration of ADP from AMP restricts the flux through ATP synthase, Complex III, and Complex IV. This results in the electrons being forced back to the complex I, which then runs in reverse, thereby generating a substantial quantity of ROS. It acts as a neutrophil chemotactic agent and inducer of the MPTP opening. Concurrently, reperfusion can also restore pH by eluting lactate, thereby relieving the inhibitory effect on MPTP opening and exacerbating calcium overload. Furthermore, reperfusion increases binding of dynamin 1-like protein (Drp1) to membrane receptors to…