Nitric Oxide Induces Cardiac Protection by Preventing Extracellular Matrix Degradation through the Complex Caveolin-3/EMMPRIN in Cardiac Myocytes.

摘要

Inhibition of Extracellular Matrix degradation by nitric oxide (NO) induces cardiac protectionagainst coronary ischemia/reperfusion (IR). Glycosylation of Extracellular Matrix MetalloproteinaseInducer (EMMPRIN) stimulates enzymatic activation of matrix metalloproteinases(MMPs) in the heart, although the mechanisms leading to EMMPRIN glycosylationare poorly understood.We sought to determine if NO may induce cardiac protection by preventingglycosylation of EMMPRIN in a mouse model of IR. Here we found that Caveolin-3binds to low glycosylated EMMPRIN (LG-EMMPRIN) in cardiac cells and in the hearts ofhealthy mice, whereas IR disrupted the complex in nitric oxide synthase 2 (NOS2) knockout(KO) mice. By contrast, the binding was partially restored when mice were fed with an NOdonor (DEA-NO) in the drinkingwater, showing a significant reduction on infarct size(NOS2KO: 34.6±5 vs NOS2KO+DEA-NO: 20.7±9), in expression of matrix metalloproteinases,and cardiac performancewas improved (left ventricular ejection fraction (LVEF).NOS2KO: 31±4 vs NOS2KO+DEA-NO: 46±6). The role of Caveolin-3/EMMPRIN in NOmediatedcardiac protectionwas further assayed in Caveolin-3 KO mice, showing no significantimprovement on infarct size (Caveolin-3 KO: 34.8±3 vs Caveolin-3 KO+DEA-NO:33.7±5), or in the expression of MMPs, suggesting that stabilization of the complex Caveolin-3/LG-EMMPRIN may play a significant role in the cardioprotective effect of NO against IR.