β3‐ Adrenergic Receptor Activation and Endoplasmic Reticulum Stress via Modulation of Intracellular Free Zn2+in Hyperglycemic Cardiomyocytes

Abstract

Beta‐adrenergic receptor (β‐AR)‐signaling plays important role in normal cardiac function while β3‐AR activation depresses cardiac contractile force. Since intracellular free Zn2+releases are originated either from metallothionin‐nitrolisation or endoplasmic reticulum (ER) and disturbing excitation‐contraction cyclying in cardiomyocytes, we examined role of β3‐AR activation on modulation of intracellular free Zn2+and ER stress (ERS) in hyperglycemic cardiomyocytes. Protein and mRNA levels of β3‐AR were increased in diabetic cardiomyocytes being associated with depressed left ventricular developed pressure. β3‐AR stimulation with BRL37344 induced significant increase in intracellular free Zn2+in diabetic cardiomyocytes which was diminished either with NOS inhibitor L‐NAME or β3‐AR antagonist SR59230 while it was further increased with non‐selective β‐blocker nadolol. Additionally, either BRL37344 or NO‐donor SNP induced significant increases in intracellular free Zn2+in normal cardiomyocytes while they were diminished either with L‐NAME or ODQ. These data are strongly demonstrated an association between increased intracellular free Zn2+ and β3‐AR activation in diabetic cardiomyocytes. BRL37344 stimulation of only diabetic cardiomyocytes presented also marked increases in ERS‐associated proteins which are very similar to those of diabetics. Taken together, our data demonstrated that β3‐AR activation in cardiomyocytes under hyperglycemia induces marked increase in intracellular free Zn2+which seems to be closely related with ERS, thereby both actions can underlie the depressed cardiac function in diabetics.(Supported by TUBITAK‐SBAG‐113S466)