MicroRNA-328 Contributes to Adverse Electrical Remodeling in Atrial Fibrillation

Abstract

Background-A characteristic of both clinical and experimental atrial fibrillation (AF) is atrial electric remodeling associated with profound reduction of L-type Ca 2ϩ current and shortening of the action potential duration. The possibility that microRNAs (miRNAs) may be involved in this process has not been tested. Accordingly, we assessed the potential role of miRNAs in regulating experimental AF. Methods and Results-The miRNA transcriptome was analyzed by microarray and verified by real-time reversetranscription polymerase chain reaction with left atrial samples from dogs with AF established by right atrial tachypacing for 8 weeks and from human atrial samples from AF patients with rheumatic heart disease. miR-223, miR-328, and miR-664 were found to be upregulated by Ͼ2 fold, whereas miR-101, miR-320, and miR-499 were downregulated by at least 50%. In particular, miR-328 level was elevated by 3.9-fold in AF dogs and 3.5-fold in AF patients relative to non-AF subjects. Computational prediction identified CACNA1C and CACNB1, which encode cardiac L-type Ca 2ϩ channel ␣1c-and ␤1 subunits, respectively, as potential targets for miR-328. Forced expression of miR-328 through adenovirus infection in canine atrium and transgenic approach in mice recapitulated the phenotypes of AF, exemplified by enhanced AF vulnerability, diminished L-type Ca 2ϩ current, and shortened atrial action potential duration. Normalization of miR-328 level with antagomiR reversed the conditions, and genetic knockdown of endogenous miR-328 dampened AF vulnerability. CACNA1C and CACNB1 as the cognate target genes for miR-328 were confirmed by Western blot and luciferase activity assay showing the reciprocal relationship between the levels of miR-328 and L-type Ca 2ϩ channel protein subunits. Conclusions-miR-328 contributes to the adverse atrial electric remodeling in AF through targeting L-type Ca 2ϩ channel genes. The study therefore uncovered a novel molecular mechanism for AF and indicated miR-328 as a potential therapeutic target for AF. (Circulation. 2010;122:2378-2387.)

Pitx2 -microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation

“…A number of profiling studies suggested potential roles for miRs in AF. For example, miR-328 expression was elevated in human AF patients and in a canine AF model although direct functional analysis of miR-328 awaits further experimentation (35). MiR-21 expression was increased in AF patients, a mouse model of spontaneous AF, and age-induced atrial fibrosis whereas miR-21 knockdown suppressed atrial fibrosis and AF promotion in rats (36,37).…”

Atrial remodeling in atrial fibrillation and association between microRNA network and atrial fibrillation

“…Furthermore CACNA1C and CACNB1, which encode the cardiac L-type Ca 2+ channel 1c-and 1 subunits, are predicted to be potential targets of miR-328. This hypothesis has been verified using adenovirus infection and a transgenic approach to force the expression of miR-328, resulting in enhanced AF vulnerability, diminished L-type Ca 2+ currents, and shortened atrial APD [29].…”

“…Unlike polymorphisms in coding genes, polymorphisms in miRNAs are closely related to various diseases, including tumors, nervous system diseases, and cardiovascular diseases. To date, thousands of miRNA genes have been found in diverse animals, with functions in regulating cell death, cell proliferation, and hematopoiesis, and even in the process of cardiovascular disease [29,30]. Increasing evidence has identified an important role for miRNAs in AF initiation and maintenance.…”

Is altered atrial microRNA-ome a critical contributor to the pathophysiology of atrial fibrillation?

“…1). Repressed translation of a 1C (Cav1.2) and b 1 (Cavb1) I Ca,L subunits by enhanced miR-328 is one potential mechanism of reduced I Ca,L in human AF [21]. The KCNQ1 gene encoding the major I Ks channel subunit contains putative binding sites for miR-1, which potentially links reduced miR-1 [13] levels with enhanced I Ks current in AF patients [3].…”

“…exchanger 1 (NCX1) as a novel target of miR-1 [17], suggesting that deregulated miR-1 may contribute to the higher NCX expression and function in AF patients [14]. However, reduced miR-1 is not a consistent finding in AF, because unaltered [21] and enhanced miR-1 levels [4] have also been reported. The reason for these inconsistent findings in atrial miR levels among studies is not known, but might reflect use of right versus left atrial tissue and differences in age, concomitant diseases and medication in the studied patient populations [5,12,29].…”