Ivabradine Induces Cardiac Protection against Myocardial Infarction by Preventing Cyclophilin-A Secretion in Pigs under Coronary Ischemia/Reperfusion

International Journal of Molecular Sciences

JoseLuis Zamorano¹  Marta Saura¹  Javier Diez-Mata²  Carlos Zaragoza²  Ignacio Hernandez²  Laura Botana²  Rafael Ramirez-Carracedo²  Laura Tesoro²  Sandra Sanchez³ 

[1] CIBER de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain;Hospital Ramón y Cajal Research Unit (IRYCIS), Cardiology Department, Universidad Francisco de Vitoria, 28223 Madrid, Spain;Systems Biology Department, Universidad de Alcala, IRYCIS, 28772 Alcala de Henares, Spain;

关键词: acute myocardial infarction;    ischemia/reperfusion;    Ivabradine;    EMMPRIN;    cyclophilin A;   

DOI  :  10.3390/ijms22062902

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown