Abstract
A long non-coding RNA (lncRNA), named myocardial infarction associated transcript (MIAT), has been documented to confer risk of myocardial infarction (MI). The aim of this study is to elucidate the pathophysiological role of MIAT in regulation of cardiac fibrosis. In a mouse model of MI, we found that MIAT was remarkably up-regulated, which was accompanied by cardiac interstitial fibrosis. MIAT up-regulation in MI was accompanied by deregulation of some fibrosis-related regulators: down-regulation of miR-24 and up-regulation of Furin and TGF-β1. Most notably, knockdown of endogenous MIAT by its siRNA reduced cardiac fibrosis and improved cardiac function and restored the deregulated expression of the fibrosis-related regulators. In cardiac fibroblasts treated with serum or angiotensin II, similar up-regulation of MIAT and down-regulation of miR-24 were consistently observed. These changes promoted fibroblasts proliferation and collagen accumulation, whereas knockdown of MIAT by siRNA or overexpression of miR-24 with its mimic abrogated the fibrogenesis. Our study therefore has identified MIAT as the first pro-fibrotic lncRNA in heart and unraveled the role of MIAT in the pathogenesis of MI. These findings also promise that normalization of MIAT level may prove to be a therapeutic option for the treatment of MI-induced cardiac fibrosis and the associated cardiac dysfunction.
Highlights
Myocardial infarction (MI) is the leading cause of death in the worldwide[1,2], which is characterized by myocardial remodeling processes involving left ventricular (LV) dilation, cardiomyocyte hypertrophy, arrhythmias, cardiac fibrosis, and cell death accompanied by altered expression of genes, leading to heart failure (HF)[3,4,5]
LncRNAs have been increasingly recognized for their roles in shaping cardiac structure and function and defining the pathogenesis of cardiovascular disease
A number of long non-coding RNA (lncRNA) have recently been identified for their roles in cardiovascular pathology[17,19,20], among which myocardial infarction associated transcript (MIAT) stands out as a attractive one as it confers risk of myocardial infarction (MI) by a genetic variant[18] and may serve as a biomarker for MI, in addition to regulating microvascular function in the setting of diabetes[21]
Summary
Myocardial infarction (MI) is the leading cause of death in the worldwide[1,2], which is characterized by myocardial remodeling processes involving left ventricular (LV) dilation, cardiomyocyte hypertrophy, arrhythmias, cardiac fibrosis, and cell death accompanied by altered expression of genes, leading to heart failure (HF)[3,4,5]. LncRNAs are mRNA-like transcripts ranging 200 to 100 kb nucleotides in length lacking protein-coding activity, yet are participating in many fundamental biological processes and pathophysiological events In addition to their relatively well-described roles in human cancers and neuronal diseases, lncRNAs have begun to be recognized for their functions in cardiovascular disease[12,13,14,15,16,17]. Our pilot study predicted that MIAT has the potential to act as a competing endogenous RNA (ceRNA) to regulate TGF-β1 expression by competing for a shared miRNA miR-24, as the former contains a sequence domain highly complementary to the latter that has been reported to be a regulator of TGF-β1 activation[11] This initial finding formed the basis of the present study and urged us to perform a series of experiments to elucidate the pathophysiological role of MIAT in MI and regulation of cardiac fibrosis as a potential mechanism
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