β 3 -adrenergic receptor activation plays an important role in the depressed myocardial contractility via both elevated levels of cellular free Zn 2+ and reactive nitrogen species


TUNCAY E., OLĞAR Y., DURAK A., DEĞİRMENCİ S., BİTİRİM C. V., TURAN B.

Journal of Cellular Physiology, vol.234, no.8, pp.13370-13386, 2019 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 234 Issue: 8
  • Publication Date: 2019
  • Doi Number: 10.1002/jcp.28015
  • Journal Name: Journal of Cellular Physiology
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.13370-13386
  • Keywords: cardiac function, confocal imaging, diabetes, intracellular zinc, metabolic syndrome, nitrosative stress, PERMEABILITY TRANSITION PORE, NITRIC-OXIDE, FUNCTIONAL BETA(3)-ADRENOCEPTOR, REPERFUSION INJURY, HEART, STIMULATION, EXPRESSION, ZINC, BETA(2)-ADRENOCEPTORS, CARDIOMYOCYTES
  • Lokman Hekim University Affiliated: No

Abstract

© 2019 Wiley Periodicals, Inc. Role of β 3 -AR dysregulation, as either cardio-conserving or cardio-disrupting mediator, remains unknown yet. Therefore, we examined the molecular mechanism of β 3 -AR activation in depressed myocardial contractility using a specific agonist CL316243 or using β 3 -AR overexpressed cardiomyocytes. Since it has been previously shown a possible correlation between increased cellular free Zn 2+ ([Zn 2+ ] i ) and depressed cardiac contractility, we first demonstrated a relation between β 3 -AR activation and increased [Zn 2+ ] i , parallel to the significant depolarization in mitochondrial membrane potential in rat ventricular cardiomyocytes. Furthermore, the increased [Zn 2+ ] i induced a significant increase in messenger RNA (mRNA) level of β 3 -AR in cardiomyocytes. Either β 3 -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 β 3 -AR activation induced depression in both Na + - and Ca 2+ -currents, the prolonged action potential (AP) seems to be associated with a marked depression in K + -currents. The β 3 -AR activation caused a negative inotropic effect on the mechanical activity of the heart, through affecting the cellular Ca 2+ -handling, including its effect on Ca 2+ -leakage from sarcoplasmic reticulum (SR). Our cellular level data with β 3 -AR agonism were supported with the data on high [Zn 2+ ] i and β 3 -AR protein-level in metabolic syndrome (MetS)-rat heart. Overall, our present data can emphasize the important deleterious effect of β 3 -AR activation in cardiac remodeling under pathological condition, at least, through a cross-link between β 3 -AR activation, NO-signaling, and [Zn 2+ ] i pathways. Moreover, it is interesting to note that the recovery in ER-stress markers with β 3 -AR agonism in hyperglycemic cardiomyocytes is favored. Therefore, how long and to which level the β 3 -AR agonism would be friend or become foe remains to be mystery, yet.