MicroRNA let-7a, -7e and -133a attenuate hypoxia-induced atrial fibrosis via targeting collagen expression and the JNK pathway in HL1 cardiomyocytes

Abstract

Abstract Background Atrial fibrillation (AF) is becoming an enormous public health challenge, and it is associated with major cardiovascular morbidity and mortality. There is a need for a better understanding of the causes and consequences of the hypoxia-related development of AF and atrial remodeling. Fibrosis is a hallmark of atrial structural remodeling. Micro-ribonucleic acids (miRNAs) have been reported to have an impact on the pathogenesis of cardiac diseases. Evidence that specific miRNAs can influence AF related to atrial structural remodeling and fibrosis via the modulation of collagens under myocardial hypoxic conditions is lacking. The aim of this study was to investigate the role of miRNAs in the modulation of fibrotic molecular mechanisms in response to hypoxic conditions, which may mediate atrial fibrosis. Methods Hypoxia was induced by cobalt chloride and hypoxia chamber respectively. MiRNA arrays were used to identify the specific miRNAs associated with the modulation of fibrotic genes. Luciferase assay, real-time polymerase chain reaction, immunofluorescence and Western blotting were used to investigate the effects of miRNAs on the expressions of the fibrotic markers collagen I and III (COL1A, COL3A) and phosphorylation levels of the stress kinase c-Jun N-terminal kinase (JNK) pathway in cultured HL-1 atrial cardiomyocytes cell line. Results COL1A and COL3A were found to be the direct regulatory targets of miR-let-7a, miR-let-7e and miR-133a in hypoxic atrial cardiac cells in vitro. The expressions of COL1A and COL3A were influenced by treatment with miRNA mimic and antagomir. The delivery of miR-133a, miR-let-7a or miR-let-7e inhibited hypoxia-induced collagen expression. The JNK pathway was critical in the pathogenesis of atrial fibrosis. Inhibition of JNK phosphorylation (JNK inhibitor SP600125) could be able to increase expression of miRNAs and repressed the fibrotic markers COL1A and COL3A which in turn might reduce the arrhythmogenic atrial remodeling. This study highlights the important role of miRNA in hypoxia-related atrial remodeling as well as atrial fibrosis. Conclusion MiRNA let-7a, miR-let-7e and miR-133a play important roles in hypoxia-related atrial fibrosis by inhibiting collagen expression and post-transcriptional repression by the JNK pathway. These novel findings may lead to the development of new therapeutic strategies. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by the grants from the Ministry of Science and Technology (MOST), Taiwan, ROC Regulation of cardiac fibrosisRegulation of collagen types by miRNAs