Abstract 14598: Ivabradine Induces Cardiac Protection by Preventing Inflammatory Response Through Inhibition of Cyclophilin-A Secretion After Myocardial Ischemia/Reperfusion Injury

• Published in: Circulation (New York, N.Y.) N.Y.), 2019-11, Vol.140 (Suppl_1 Suppl 1), p.A14598-A14598
• Main Authors: Hernandez Navarro, Ignacio, Ramirez-Carracedo, Rafael, Tesoro, Laura, Diez Mata, Javier, Garcia De la P, Ricardo, Reventun, Paula, Zamorano, Jose L, Saura, Marta, Zaragoza, Carlos
• Format: Article
• Language: English
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circ.140.suppl_1.14598

IntroductionInflammation and extracellular matrix proteolysis contribute with abnormal cardiac remodeling after ischemia/reperfusion injury. The binding of secreted Cyclophilin-A (CypA) with its ligand Extracellular-Matrix-Metalloproteinase-Inducer EMMPRIN, plays a pivotal role by inducing a cascade of pro-inflammatory gene expression, including matrix metalloproteinases (MMPs).HypothesisWe found that ivabradine regulates the levels of EMMPRIN-induced, MMP-9 in the hearts subjected to ischemia/reperfusion, by unknown mechanisms. We postulate that ivabradine may promote cardiac protection by reducing the secretion of CypA and, thus preventing the complex CyPA/EMMPRIN.Methods and ResultsIn a porcine model of balloon occlusion of the anterior descending coronary artery, we found that ivabradine (N=10; 0.5 mg/kg) significantly increased tissue levels of CypA when compared to placebo (5.2 ± 1.67 ivabradine vs 1.27 ± 1.29 Placebo), as detected by immunoblot and confocal microscopy. By contrast, plasma levels of CypA were reduced by day 7 in the necrotic areas (113 ± 3.05 Placebo vs 53 ± 2.11 ivabradine), while in the heart, CyPA was mostly bound to low glycosylated forms of EMMPRIN, thus preventing EMMPIN-induced expression/activity of MMP9. To test whether ivabradine may regulate CypA secretion, confocal microscopy detection of CyPA in cardiac cell cultures treated with ivabradine, have shown a significant reduction in CyPA forming vesicles, as detected by co-localization with the secretion marker VAMP.ConclusionsIvabradine preserves heart integrity by targeting the release of the proinflammatory CyPA, it regulates inflammation through the complex CyPA/EMMPRIN by preserving EMMPRIN in a low glycosylation stage. Extensive investigation will be required to validate this new functionality of ivabradine.