Rasagiline antiremodeling action after myocardial infarction may be mediated by circadian rhythm and neurotrophic related gene expression changes

Abstract

Rasagiline mesylate (RG) is a potent, selective, irreversible monoamine oxidase-B inhibitor, developed to prolong the action of dopamine in the brain. It may rescue degenerating dopamine neurons through inhibiting death signal transduction initiated by the mitochondria permeability transition pore. We have previously shown that it decreases post-experimental infarct remodeling (REM). We investigated whether this cardioprotective result could be due to centrally mediated actions. In a rat model undergoing experimental myocardial infarction (MI) by a permanent ligation of the left anterior descending coronary artery. RG was administered, intraperitoneally for 28 days (2 mg/kg) starting 24 hours after MI induction. Treatment with RG significantly ameliorated cardiac REM echocardiographically as we have previously shown. In order to identify potential new cardioprotective mechanisms of RG action after MI, a comparative RNA expression analysis of remote region cardiac tissue was performed in placebo (Normal saline- NS), RG and Sham samples. RNA-seq analysis results were also confirmed by real time PCR. Our analysis showed: – differential RNA expression of circadian rhythm in NS samples versus RG. Circadian related genes Per3, Ciart, Dbp, Hpd, Nr1d2, and Rev-erb were upregulated while Arntl gene was downregulated (all P < 0.01); – as regards neurotrophic genes, neuropeptide Y (Npy) and neurogranin (Nrgn) genes were downregulated in RG samples compared to NS while the Brain-Derived Neurotrophic Factor (Bdnf) was upregulated (all P < 0.01). Our findings indicate that MI injury influences in a protective manner the expression of circadian rhythm and neurotrophic factor genes in cardiac tissue; potential regulation of these genes is part of the novel cardioprotective mechanism of RG action described, further advocating the possible use of this drug post-MI.