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.

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 and reactive nitrogen species 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. © 2019 Wiley Periodicals, Inc.

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