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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
Author(s) -
Tuncay Erkan,
Olgar Yusuf,
Durak Aysegul,
Degirmenci Sinan,
Bitirim Ceylan Verda,
Turan Belma
Publication year - 2019
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.28015
Subject(s) - contractility , medicine , reactive nitrogen species , nitric oxide , inotrope , reactive oxygen species , endocrinology , chemistry , agonist , nitric oxide synthase , receptor , biology , biochemistry
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.