Nitric Oxide Induces Cardiac Protection by Preventing Extracellular Matrix Degradation through the Complex Caveolin-3/EMMPRIN in Cardiac Myocytes.
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2016-09-20
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PLOS One
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Abstract
Inhibition of Extracellular Matrix degradation by nitric oxide (NO) induces cardiac protection
against coronary ischemia/reperfusion (IR). Glycosylation of Extracellular Matrix Metalloproteinase
Inducer (EMMPRIN) stimulates enzymatic activation of matrix metalloproteinases
(MMPs) in the heart, although the mechanisms leading to EMMPRIN glycosylation
are poorly understood.We sought to determine if NO may induce cardiac protection by preventing
glycosylation of EMMPRIN in a mouse model of IR. Here we found that Caveolin-3
binds to low glycosylated EMMPRIN (LG-EMMPRIN) in cardiac cells and in the hearts of
healthy 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 NO
donor (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 NOmediated
cardiac protectionwas further assayed in Caveolin-3 KO mice, showing no significant
improvement 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.