Diacetoxymethyl malonate (MAM) administered at reperfusion significantly reduced infarct size compared to control in a mouse model of cardiac ischemia-reperfusion injury.
Does the rapidly hydrolysed malonate prodrug MAM reduce infarct size and mitochondrial ROS production in a mouse model of acute myocardial infarction when administered at reperfusion?
The rapidly hydrolysed malonate prodrug MAM protects against cardiac ischemia/reperfusion injury when administered at reperfusion in a mouse model, suggesting potential clinical utility for patients undergoing primary percutaneous coronary intervention.
p-value: p=<0.05
PURPOSE: Mitochondrial reactive oxygen species (ROS) production upon reperfusion of ischemic tissue initiates the ischemia/reperfusion (I/R) injury associated with heart attack. During ischemia, succinate accumulates and its oxidation upon reperfusion by succinate dehydrogenase (SDH) drives ROS production. Inhibition of succinate accumulation and/or oxidation by dimethyl malonate (DMM), a cell permeable prodrug of the SDH inhibitor malonate, can decrease I/R injury. However, DMM is hydrolysed slowly, requiring administration to the heart prior to ischemia, precluding its administration to patients at the point of reperfusion, for example at the same time as unblocking a coronary artery following a heart attack. To accelerate malonate delivery, here we developed more rapidly hydrolysable malonate esters. METHODS: We synthesised a series of malonate esters and assessed their uptake and hydrolysis by isolated mitochondria, C2C12 cells and in mice in vivo. In addition, we assessed protection against cardiac I/R injury by the esters using an in vivo mouse model of acute myocardial infarction. RESULTS: We found that the diacetoxymethyl malonate diester (MAM) most rapidly delivered large amounts of malonate to cells in vivo. Furthermore, MAM could inhibit mitochondrial ROS production from succinate oxidation and was protective against I/R injury in vivo when added at reperfusion. CONCLUSIONS: The rapidly hydrolysed malonate prodrug MAM can protect against cardiac I/R injury in a clinically relevant mouse model.
Prag et al. (Thu,) conducted a other in Cardiac Ischemia-Reperfusion Injury. Diacetoxymethyl malonate (MAM) vs. 0.9% saline was evaluated on Infarct size (% of risk area) (p=<0.05). Diacetoxymethyl malonate (MAM) administered at reperfusion significantly reduced infarct size compared to control in a mouse model of cardiac ischemia-reperfusion injury.