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Abstract
BackgroundHeart failure (HF) is a clinical syndrome characterized by left ventricular dysfunction or elevated intracardiac pressures. Research supports that microRNAs (miRs) participate in HF by regulating targeted genes. Hence, the current study set out to study the role of HDAC3-medaited miR-18a in HF by targeting ADRB3.MethodsFirstly, HF mouse models were established by ligation of the left coronary artery at the lower edge of the left atrial appendage, and HF cell models were generated in the cardiomyocytes, followed by ectopic expression and silencing experiments. Numerous parameters including left ventricular posterior wall dimension (LVPWD), interventricular septal dimension (IVSD), left ventricular end diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LEVDP), heart rate (HR), left ventricular pressure rise rate (+ dp/dt) and left ventricular pressure drop rate (-dp/dt) were measured in the mice. In addition, apoptosis in the mice was detected by means of TUNEL staining, while RT-qPCR and Western blot analysis were performed to detect miR-18a, HDAC3, ADRB3, cMyb, MMP-9, Collagen 1 and TGF-β1 expression patterns. Dual luciferase reporter assay validated the targeting relationship between ADRB3 and miR-18a. Cardiomyocyte apoptosis was determined by means of flow cytometry.ResultsHDAC3 and ADRB3 were up-regulated and miR-18a was down-regulated in HF mice and cardiomyocytes. In addition, HDAC3 could reduce the miR-18a expression, and ADRB3 was negatively-targeted by miR-18a. After down-regulation of HDAC3 or ADRB3 or over-expression of miR-18a, IVSD, LVEDD, LVESD and LEVDP were found to be decreased but LVPWD, LVEF, LVFS, LVSP, + dp/dt, and −dp/dt were all increased in the HF mice, whereas fibrosis, hypertrophy and apoptosis of HF cardiomyocytes were declined.ConclusionCollectively, our findings indicate that HDAC3 silencing confers protection against HF by inhibiting miR-18a-targeted ADRB3.
Highlights
Heart failure (HF) is a clinical syndrome characterized by left ventricular dysfunction or elevated intracardiac pressures
Results miR‐18a was under‐expressed in HF mice and miR‐18a overexpression could improve HF in mice Firstly, mouse models of HF were established in order to investigate whether miR-18a was involved in alleviation of HF
The results of echocardiography demonstrated that LVP, left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were decreased in HF mice, while interventricular septal dimension (IVSD), left ventricular end diastolic diameter (LVEDD) and left ventricular end systolic diameter (LVESD) were increased
Summary
Heart failure (HF) is a clinical syndrome characterized by left ventricular dysfunction or elevated intracardiac pressures. The declining expression of various circulating miRs have been closely related with worsening acuity of HF [8]. One such miR, namely miR-18a, has been closely-associated with HF by numerous authors. Decreased expression of HDAC3 was associated with improved cardiac function of mice with left ventricular HF [13]. Initial bioprediction findings in our study indicated the adrenergic-receptor β3 (ADRB3) gene as a target of miR-18a. ADRB3 has been identified to be closely associated with cardiac diseases like HF. ADRB3 could facilitate the development of left ventricular diastolic dysfunction, which is a critical cause of HF [16]
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