New mechanisms of protection of cardiomyocytes from ischemia / reperfusion injury

Cardiovascular diseases are a major problem of public health management. Ischemic and pharmacological pre and postconditioning should significantly improve the prognosis of patients suffering from myocardial ischemia/reperfusion. However, the morbi-mortality of these patients is still high and research must remain active. The first results of myocardial stem cell therapy show that we cannot regenerate myocardium but a recent meta-analysis reported positive effects that can be explained through a paracrine mechanism. Mesenchymal stem cells protect ischemic cardiomyocytes from reperfusion injury through a paracrine activation of the PI3kinase/Akt pathway in a similar way to ischemic postconditioning. The mediators of this protection could be growth factors such as VEGF or IGF-1 though we couldn’t demonstrate a direct effect of one or the other. Modulating the activity of the ATP synthase during ischemia is another promising therapeutic target. This enzyme reverses its activity and hydrolyses ATP when the supply in oxygen is impaired. This leads to the reduction of the cellular pool of ATP and accelerates cell death. We identified new small molecules with a similar effect to IF1 that can selectively inhibit the reverse activity of the ATP synthase, preserve ATP and thus increase cell survival in a preconditioning-like effect. These two different techniques could be part of the therapeutic arsenal against ischemia/reperfusion in the next decades.