β3 -adrenergic receptor activation plays an important role in the depressed myocardial contractility via both elevated levels of cellular free Zn2+ and reactive nitrogen species

J Cell Physiol. 2019 Aug;234(8):13370-13386. doi: 10.1002/jcp.28015. Epub 2019 Jan 5.

Abstract

Role of β3 -AR dysregulation, as either cardio-conserving or cardio-disrupting mediator, remains unknown yet. Therefore, we examined the molecular mechanism of β3 -AR activation in depressed myocardial contractility using a specific agonist CL316243 or using β3 -AR overexpressed cardiomyocytes. Since it has been previously shown a possible correlation between increased cellular free Zn2+ ([Zn2+ ]i ) and depressed cardiac contractility, we first demonstrated a relation between β3 -AR activation and increased [Zn2+ ]i , parallel to the significant depolarization in mitochondrial membrane potential in rat ventricular cardiomyocytes. Furthermore, the increased [Zn2+ ]i induced a significant increase in messenger RNA (mRNA) level of β3 -AR in cardiomyocytes. Either β3 -AR activation or its overexpression could increase cellular reactive oxygen species (ROS) and reactive nitrogen species (RNS) levels, in line with significant changes in nitric oxide (NO)-pathway, including increases in the ratios of pNOS3/NOS3 and pGSK-3β/GSK-3β, and PKG expression level in cardiomyocytes. Although β3 -AR activation induced depression in both Na+ - and Ca2+ -currents, the prolonged action potential (AP) seems to be associated with a marked depression in K+ -currents. The β3 -AR activation caused a negative inotropic effect on the mechanical activity of the heart, through affecting the cellular Ca2+ -handling, including its effect on Ca2+ -leakage from sarcoplasmic reticulum (SR). Our cellular level data with β3 -AR agonism were supported with the data on high [Zn2+ ]i and β3 -AR protein-level in metabolic syndrome (MetS)-rat heart. Overall, our present data can emphasize the important deleterious effect of β3 -AR activation in cardiac remodeling under pathological condition, at least, through a cross-link between β3 -AR activation, NO-signaling, and [Zn2+ ]i pathways. Moreover, it is interesting to note that the recovery in ER-stress markers with β3 -AR agonism in hyperglycemic cardiomyocytes is favored. Therefore, how long and to which level the β3 -AR agonism would be friend or become foe remains to be mystery, yet.

Keywords: cardiac function; confocal imaging; diabetes; intracellular zinc; metabolic syndrome; nitrosative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-3 Receptor Agonists / pharmacology
  • Animals
  • Calcium Signaling
  • Cell Line
  • Dioxoles / pharmacology
  • Male
  • Membrane Potential, Mitochondrial
  • Metabolic Syndrome / metabolism
  • Models, Cardiovascular
  • Myocardial Contraction / drug effects
  • Myocardial Contraction / physiology*
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Phosphorylation
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Wistar
  • Reactive Nitrogen Species / metabolism*
  • Reactive Oxygen Species / metabolism
  • Receptors, Adrenergic, beta-3 / genetics
  • Receptors, Adrenergic, beta-3 / metabolism*
  • Zinc / metabolism*

Substances

  • Adrenergic beta-3 Receptor Agonists
  • Dioxoles
  • RNA, Messenger
  • Reactive Nitrogen Species
  • Reactive Oxygen Species
  • Receptors, Adrenergic, beta-3
  • disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate
  • Zinc