Background: In recent decades, research on myocardial ischemia/reperfusion injury has focused on cardiomyocytes. However, both cardiomyocytes and coronary arteries, especially the microvasculature, are injured during acute myocardial infarction. Microvascular damage has been shown to affect patients’ prognosis, independent of infarct size. In cardiomyocytes, changes in mitochondrial dynamics is one response to ischemia/reperfusion injury, and this shift in mitochondrial dynamics is thought to contribute to cardiomyocyte ischemia/reperfusion injury. Preliminary in vitro studies in endothelial cells established a link between mitochondrial dynamics and ischemia/reperfusion-induced endothelial cell damage. However, it remains unclear whether mitochondrial dynamics in endothelial cells influence microvascular (dys)function after ischemia/reperfusion.
Aim: To investigate the effect of an increased endothelium-specific mitochondrial fission mediator dynamin-related protein 1 (Drp1) expression on infarct size and microvascular damage (no-reflow).
Methods: Isolated perfused hearts from endothelial-specific Drp1-overexpressing (eDRP1-OE; n=14) or littermate control (eDRP1-control; n=10) Sprague-Dawley rats were subjected to 30 min regional ischemia by occlusion of the left anterior descending coronary artery followed by 120 min reperfusion. Patent blue was used to delineate the area at risk, triphenyl tetrazolium chloride to stain infarct size, and thioflavin-S to visualize microvascular injury.
Results: Area at risk (51±8 vs. 48±7% left ventricle; p=0.524) and infarct size (44±10 vs. 45±9% area at risk; p=0.663, respectively) were comparable between eDRP1-OE and -control hearts. The area of no-reflow was increased in eDrp1-OE compared to the eDRP1-control hearts (7.3±5.3 vs. 3.1±2.5% area at risk; p=0.030).
Conclusion: Our results provide first evidence of a causal relationship between the shift in mitochondrial dynamics towards increased mitochondrial fission in endothelial cells and microvascular damage by myocardial ischemia/reperfusion. This suggests that mitochondria might be a promising target for cardioprotective interventions, not only in cardiomyocytes but also in endothelial cells.
