The crosstalk of HDAC3, microRNA-18a and ADRB3 in the progression of heart failure

Abstract

Background Heart 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. Methods Firstly, 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. Results HDAC3 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. Conclusion Collectively, our findings indicate that HDAC3 silencing confers protection against HF by inhibiting miR-18a-targeted ADRB3.

Expression and Regulation Network of HDAC3 in Acute Myeloid Leukemia and the Implication for Targeted Therapy Based on Multidataset Data Mining

“…HDAC can remove acetyl groups from the amino terminus of lysine residues on histones, while histone acetyltransferases (HATS) promote the addition of lysine residues, leading to structural changes in local chromatin [8,[39][40][41], which is an important step in regulating protein entry into DNA [7]. Studies have shown that HDAC and HATS enzymes are involved in the regulation of transcription Computational and Mathematical in Medicine factors, transcription modulators, and DNA repair proteins [42].…”

“…Histone deacetylase (HDAC) is a kind of regulation of histone acetylation by protease, the enzyme can be removed from lysine acetyl, and most of the work, by protein complexes formed, is the modification of the chromosome structure and gene expression regulation and control important regulatory factors [ 7 , 8 ]. Conversely, deacetylation can also lead to transcriptional inhibition and impaired hematopoietic differentiation.…”

MiR-29a Increase in Aging May Function as a Compensatory Mechanism Against Cardiac Fibrosis Through SERPINH1 Downregulation

“…Within this cluster, miR-18a was reported to regulate the expression of several extracellular matrix proteins ( 22 ) and its decreased expression in heart failure in the aged individuals was linked to aging-induced heart remodeling. Corroborating to this, downregulation of miR-18a was associated with increased fibrosis and a decline in heart function ( 23 ), while over-expression of miR-18a reduced fibrosis, hypertrophy, and the apoptosis of cardiomyocytes in heart failure ( 24 ).…”

The critical roles of histone deacetylase 3 in the pathogenesis of solid organ injury

“…In addition, HDAC3 has been shown to promote heart failure and dietary death by exacerbating metabolic disturbances in mitochondria in the cardiomyocytes of mice fed with a high-fat diet [ 78 ]. Mechanically, HDAC3 inhibition prevented heart failure by inhibiting miR-18a-targeted adrenergic-receptor β3 [ 79 ]. HDAC3 expression and activation in cardiomyocytes were also regulated by Ca 2+ /calmodulin-dependent kinase II (CaMKII).…”