Abstract 19684: Nitric Oxide Protects From Cardiac Ischemia/reperfusion Damage by Blocking Activation of Extracellular Matrix Metalloproteinase Inducer EMMPRIN Through Binding to Caveolin3
Introduction: Nitric Oxide (NO) induces cardiac protection by still unknown mechanisms. We previously found that Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) is a target of NO during ischemia/reperfusion (IR). Hypothesis: EMMPRIN is glycosylated at different locations, and high glycosylated forms of EMMPRIN are required for matrix metalloproteinase downstream activation in several cell types. In hearts subject to IR NO may inhibit EMMPRIN glycosylation.
Methods: A surgical model of coronary artery occlusion.
Results: We found that iNOS null mice show high glycosylated (active) forms of EMMPRIN, whereas NO producing mice also show low glycosylated EMMPRIN. Likewise, NO producing mice exhibit a significant level of cardiac protection, as shown by increased left ventricle ejection fraction detected by high frequency ultrasound, and decreased area of infarction as shown by ex vivo TTC staining. To test whether low glycosylated forms of EMMPRIN may play a role in iNOS WT cardiac protection, we found that EMMPRIN binds to caveolin-3 in healthy hearts, however, I/R prompted the disruption of low glycosylated EMMPRIN from caveolin-3 in iNOS null mice in a time dependent manner whereas a significant low glycosylated portion of EMMPRIN remained bound to caveolin-3 in iNOS WT mice. To study this effect in more detail, we found that caveolin-3 binding to low glycosylated forms of EMMPRIN, prevents downstream EMMPRIN-mediated extracellular matrix degradation through matrix metalloproteinase activation. I/R damage resulted more severe in caveolin-3 null mice, where no low glycosylated EMMPRIN was detected after reperfusion. Conclusions: We show for the first time that caveolin-3 induces nitric oxide mediated cardiac protection by preventing glycosylation of EMMPRIN in mouse hearts.
- Ischemia/Reperfusion injury
- Extracellular MMP Inducer EMMPRIN
- Nitric Oxide
- Acute Myocardial Infarction
Author Disclosures: I. Cuadrado: None. A.M. Martin: None. M. Saura: None. J.L. Zamorano: None. C. Zaragoza: None.
- © 2015 by American Heart Association, Inc.