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

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.