Mitochondrial respiration and microRNA expression in right and left atrium of patients with atrial fibrillation

Abstract

Atrial fibrillation (AF) is the most common cardiac arrhythmia with a potential to cause serious complications. Mitochondria play central roles in cardiomyocyte function and have been implicated in AF pathophysiology. MicroRNA (miR) are suggested to influence both mitochondrial function and the development of AF. Yet mitochondrial function and miR expression remain largely unexplored in human atrial tissue. This study aims to investigate mitochondrial function and miR expression in the right (RA) and left atria (LA) of patients with AF and sinus rhythm (SR). Myocardial tissue from the RA and LA appendages was investigated in 37 patients with AF (n = 21) or SR (n = 16) undergoing coronary artery bypass surgery and/or heart valve surgery. Mitochondrial respiration was measured in situ after tissue permeabilization by saponin. MiR expression was assessed by miR array and real-time quantitative reverse-transcription polymerase chain reaction. Maximal mitochondrial respiratory rate was increased in both RA and LA tissue of patients with AF vs. SR. Biatrial downregulation of miR-208a and upregulation of miR-106b, -144, and -451 were observed in AF vs. SR. In addition, miR-15b was upregulated in AF within RA only, and miR-106a, -18a, -18b, -19a, -19b, -23a, -25, -30a, -363, -486-5p, -590-5p, and -93 were upregulated in AF within LA only. These findings suggest that mitochondrial function and miR are involved in AF pathophysiology and should be areas of focus in the exploration for potential novel therapeutic targets.

Molecular inotropy mediated by cardiac miR-based PDE4D/PRKAR1α/phosphoprotein signaling

“…Taken together, a combination of non-canonical miR/mRNA interactions, and/or indirect effects, mediates the PRKAR1α suppression in rodent myocytes. Moreover, targeted miR-208a suppression and consequent reduced phospho-cTnI/PLN content may account for the earlier observation that loss of cardiac specific miR-208a and cardiac enriched miRs leads to dilated cardiomyopathy and heart failure161723246061.…”

“…Accordingly, there is an urgent need to discover new inotropic agents with unique mechanisms of action for enhancing cardiac contractility4. MicroRNAs (miRs), which are highly conserved non-coding small RNAs that regulate gene expression567, are known to affect heart development and growth89101112 and are altered in cardiac disease1314151617. However, little is known whether a direct or indirect pathway exists between miRs and their targets influencing cardiac myocyte performance.…”

“…Down-regulation of the fast MYH6 isoform is linked to failing human heart performance21 and direct MYH6 gene transfer boosts failing myocyte contractility22. The MYH6 gene embeds the cardiac restricted miR-208a whose expression, like the host gene, can be depressed in chronic heart disease16172324. It is unclear, however, whether cardiac specific miR-208a has a direct or indirect effect on cardiac function independent of host gene myosin effects.…”

“…It is unclear, however, whether cardiac specific miR-208a has a direct or indirect effect on cardiac function independent of host gene myosin effects. In humans, miR-208a is significantly down-regulated in patients with atrial fibrillation (AF)17 and with chronic cardiomyopathy24. In rodents, chronic miR-208a deficiency is reported to cause heart performance deficits2526 and chronic transgenic overexpression of miR-208a induces arrhythmias in the absence of sarcomere structural alterations25.…”

A New Insight into the Molecular Mechanism of Atrial Fibrillation: The Role of MicroRNAs

“…Other studies have shown significant differences between the expression of microRNAs in the right and left atria [13,14]. In one study, 136 different expressions of microRNAs were found in patients with atrial fibrillation and mitral stenosis compared to healthy controls [15].…”