Previous studies have shown the role of microRNA (miR)-19 in aging-related heart failure. The present study aimed to verify the effects of miR-19 on cardiac fibrosis and its target.
Cardiac fibrosis was induced by myocardial infarction (MI)-induced heart failure and angiotensin (Ang) II-treated rats in vivo , and was induced in Ang II-treated cardiac fibroblasts (CFs) in vitro .
The expression of miR-19 was reduced in the heart tissue of MI and Ang II-treated rats, and Ang II-treated CFs. The impaired cardiac function in rats was repaired after miR-19 administration. The levels of collagen I, collagen III and transforming growth factor-beta (TGF-β) increased in the heart tissue of MI and Ang II-treated rats, and Ang II-treated CFs. These increases were reversed by miR-19 agomiR. Moreover, the bioinformatic analysis and luciferase reporter assays demonstrated that connective tissue growth factor (CTGF) was a direct target of miR-19. MiR-19 treatment inhibited CTGF expression in CFs, while CTGF overexpression inhibited miR-19 agomiR to attenuate the Ang II-induced increases of collagen I and collagen III in CFs. The increases of p-ERK, p-JNK and p-p38 in the CFs induced by Ang II were repressed by miR-19 agomiR.
Upregulating miR-19 can improve cardiac function and attenuate cardiac fibrosis by inhibiting the CTGF and MAPK pathways.
Heart failure is caused by multiple factors, and some of them, such as obesity, diabetes and hypertension, are interconnected.
In the case of heart failure, electrical conduction, energy metabolism and cardiac contractility are disrupted, all disabling the heart to fulfill its circulatory roles. , Heart failure is preceded by adverse left ventricle (LV) remodeling, as manifested by hypertrophy or dilatation. , Cardiac fibrosis is a key driver of chronic heart failure. , In addition, excessive cardiac fibrosis causes large infarction that impair cardiac function. , Cardiac fibrosis is characterized by the accumulation of extracellular matrix in the myocardium. Cardiac fibroblasts (CFs) are major participators in fibrosis, ,
but their mechanisms remain poorly understood.
MicroRNAs (miRs), a group of small and non-coding RNAs, can bind to the complementary 3’-untranslated region to inhibit messenger RNA (mRNA) translation, thus negatively regulating gene expression at the post-transcriptional level.
Many miRNAs play pathogenic roles in processes of heart failure, such as apoptosis, remodeling, hypoxia, or hypertrophy. , In aging-associated heart failure, the expression level of miR-19 decreased, but in heart failure-resistant mice, this level increased.
The effects of miR-19 on cardiac fibrosis and associated mechanisms are still unclear.
Connective tissue growth factor (CTGF) is a cysteine-rich matricellular protein involved in various biological processes, such as cell adhesion, angiogenesis, proliferation and differentiation, as well as tissue fibrosis.
CTGF monoclonal antibody can repair the infarcted tissue and attenuate LV hypertrophy and fibrosis to enhance survival and LV function. MiR-19 can modulate the expression of extracellular matrix proteins and CTGF in cardiomyocytes. The purpose of this study was to explore the cardioprotective effects of miR-19 in rats with MI-induced heart failure and associated regulatory mechanisms.