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.
Highlights
In pigs injected with 0.3 mg/kg Ivabradine, a cardiac ultrasound was used to find that the left ventricle ejection fraction (LVEF) was significantly improved, when compared to a placebo, by day 7 after IR (Figure 1A) as a result of a reduction in the necrotic area
We show an underlying mechanism to prevent the inflammatory response elicited by cardiac IR in response to Ivabradine
CyPA is an intracellular protein that is expressed under inflammatory conditions by several cell types; some of them have been shown to secrete CyPA during in the early stages of pathologies that include atherosclerosis, coronary artery disease (CAD), and acute myocardial infarction [11]
Summary
Cardiac remodeling is the result of an orchestrated series of genomic, biochemical, and morphological changes which determine the heart’s fate in terms of restoring adequate heart contractility. Adverse cardiac remodeling may result in severe and chronic heart failure by still unknown molecular events, and intense research on finding new diagnostic and forecast molecular targets is of a significant interest. Ivabradine is designed to target cardiac funny current (I(f)) by inhibiting the activity of hyperpolarization-activated cyclic nucleotide (HCN)-gated potassium channels, reducing heart rate with no significant effect on blood pressure and cardiac output. We and others have confirmed that Ivabradine is effective against dobutamine-induced tachycardia in a cardiac shock (CS) model, improves the hemodynamic parameters immediately after acute myocardial infarction (AMI) and in the long term [2,3], and inhibits extracellular matrix metalloproteinase inducer (EMMPRIN) activity in a porcine model of coronary ischemia/reperfusion (IR), but the underlying molecular pathways are yet to be understood
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