Depletion of β3-adrenergic receptor induces left ventricular diastolic dysfunction via potential regulation of energy metabolism and cardiac contraction

Gene. 2019 May 20:697:1-10. doi: 10.1016/j.gene.2019.02.038. Epub 2019 Feb 19.

Abstract

Left ventricular diastolic dysfunction (LVDD) is a central perturbation in heart failure with preserved ejection fraction, and there are currently no effective remedies to improve LVDD in clinical practice. The β3-adrenergic receptor (ADRB3) was reported to play protective effects on inhibiting myocardial fibrosis in response to hemodynamic stress. However, the effects of ADRB3 on LVDD and its underlying mechanisms are still undefined. In the current study, the role of ADRB3 in LVDD was identified in ADRB3-knockout mice. Echocardiography parameters showed that depletion of ADRB3 had little effect on cardiac systolic function but obviously led to cardiac diastolic dysfunction in vivo. Proteomics (including the global proteome, phosphorylated and acetylated proteome) and bioinformatics analysis (including GO analysis, KEGG pathway analysis, GO-Tree network, Pathway-Act network, and protein-protein interaction network) were performed on cardiac specimens of ADRB3-KO mice and wild-type mice. The results showed that the cardiac energy metabolism (especially the citrate cycle), actin cytoskeleton organization, and cardiac muscle contraction (related to mitogen-activated protein kinase, toll-like receptor, and ErbB signalling pathway) were potential core mechanisms underlying ADRB3-KO-induced LVDD. In addition, the protein-protein interaction network indicated that the core proteins associated with ADRB3-KO-induced LVDD were FGG, ALDH1A1, FGA, APOC3, SLC4A1, SERPINF2, HP, CTNNB1, and TKT. In conclusion, the absence of ADRB3 leads to LVDD, which is potentially associated with the regulation of cardiac energy metabolism, actin cytoskeleton organization, and cardiac muscle contraction.

Keywords: ADRB3; Bioinformatics analysis; Cardiac muscle contraction; Energy metabolism; Left ventricular diastolic dysfunction.

MeSH terms

  • Animals
  • Blood Pressure / physiology
  • Cardiomyopathies
  • Diastole
  • Echocardiography
  • Energy Metabolism / genetics
  • Gene Ontology
  • Heart Failure
  • Hemodynamics
  • Male
  • Mice
  • Mice, Knockout
  • Myocardial Contraction
  • Proteomics
  • Receptors, Adrenergic
  • Receptors, Adrenergic, beta-3 / genetics*
  • Receptors, Adrenergic, beta-3 / physiology*
  • Signal Transduction
  • Stroke Volume
  • Systole
  • Ventricular Dysfunction, Left / genetics
  • Ventricular Dysfunction, Left / physiopathology*
  • Ventricular Function, Left / genetics
  • Ventricular Function, Left / physiology

Substances

  • Receptors, Adrenergic
  • Receptors, Adrenergic, beta-3