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Ivabradine Induces Cardiac Protection against Myocardial Infarction by Preventing Cyclophilin-A Secretion in Pigs under Coronary Ischemia/Reperfusion
Authors:Ignacio Hernandez  Laura Tesoro  Rafael Ramirez-Carracedo  Javier Diez-Mata  Sandra Sanchez  Marta Saura  Jose Luis Zamorano  Carlos Zaragoza  Laura Botana
Affiliation:1.Hospital Ramón y Cajal Research Unit (IRYCIS), Cardiology Department, Universidad Francisco de Vitoria, 28223 Madrid, Spain; (I.H.); (L.T.); (R.R.-C.); (J.D.-M.); (L.B.);2.CIBER de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; (M.S.); (J.L.Z.);3.Systems Biology Department, Universidad de Alcala, IRYCIS, 28772 Alcala de Henares, Spain;4.Cardiology Department, Hospital Ramón y Cajal, IRYCIS, 28034 Madrid, Spain
Abstract:In response to cardiac ischemia/reperfusion, proteolysis mediated by extracellular matrix metalloproteinase inducer (EMMPRIN) and its secreted ligand cyclophilin-A (CyPA) significantly contributes to cardiac injury and necrosis. Here, we aimed to investigate if, in addition to the effect on the funny current (I(f)), Ivabradine may also play a role against cardiac necrosis by reducing EMMPRIN/CyPA-mediated cardiac inflammation. In a porcine model of cardiac ischemia/reperfusion (IR), we found that administration of 0.3 mg/kg Ivabradine significantly improved cardiac function and reduced cardiac necrosis by day 7 after IR, detecting a significant increase in cardiac CyPA in the necrotic compared to the risk areas, which was inversely correlated with the levels of circulating CyPA detected in plasma samples from the same subjects. In testing whether Ivabradine may regulate the levels of CyPA, no changes in tissue CyPA were found in healthy pigs treated with 0.3 mg/kg Ivabradine, but interestingly, when analyzing the complex EMMPRIN/CyPA, rather high glycosylated EMMPRIN, which is required for EMMPRIN-mediated matrix metalloproteinase (MMP) activation and increased CyPA bonding to low-glycosylated forms of EMMPRIN were detected by day 7 after IR in pigs treated with Ivabradine. To study the mechanism by which Ivabradine may prevent secretion of CyPA, we first found that Ivabradine was time-dependent in inhibiting co-localization of CyPA with the granule exocytosis marker vesicle-associated membrane protein 1 (VAMP1). However, Ivabradine had no effect on mRNA expression nor in the proteasome and lysosome degradation of CyPA. In conclusion, our results point toward CyPA, its ligand EMMPRIN, and the complex CyPA/EMMPRIN as important targets of Ivabradine in cardiac protection against IR.
Keywords:acute myocardial infarction  ischemia/reperfusion  Ivabradine  EMMPRIN  cyclophilin A
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