Distinct Effects of Mitochondrial Na + /Ca 2+ Exchanger Inhibition and Ca 2+ Uniporter Activation on Ca 2+ Sparks and Arrhythmogenesis in Diabetic Rats

Abstract

Background Mitochondrial dysfunction contributes to the cardiac remodeling triggered by type 2 diabetes (T2D). Mitochondrial Ca 2+ concentration ([Ca 2+ ] m ) modulates the oxidative state and cytosolic Ca 2+ regulation. Thus, we investigated how T2D affects mitochondrial Ca 2+ fluxes, the downstream consequences on myocyte function, and the effects of normalizing mitochondrial Ca 2+ transport. Methods and Results We compared myocytes/hearts from transgenic rats with late‐onset T2D (rats that develop late‐onset T2D due to heterozygous expression of human amylin in the pancreatic β‐cells [HIP] model) and their nondiabetic wild‐type (WT) littermates. [Ca 2+ ] m was significantly lower in myocytes from diabetic HIP rats compared with WT cells. Ca 2+ extrusion through the mitochondrial Na + /Ca 2+ exchanger (mitoNCX) was elevated in HIP versus WT myocytes, particularly at moderate and high [Ca 2+ ] m , while mitochondrial Ca 2+ uptake was diminished. Mitochondrial Na + concentration was comparable in WT and HIP rat myocytes and remained remarkably stable while manipulating mitoNCX activity. Lower [Ca 2+ ] m was associated with oxidative stress, increased sarcoplasmic reticulum Ca 2+ leak in the form of Ca 2+ sparks, and mitochondrial dysfunction in T2D hearts. MitoNCX inhibition with CGP‐37157 reduced oxidative stress, Ca 2+ spark frequency, and stress‐induced arrhythmias in HIP rat hearts while having no significant effect in WT rats. In contrast, activation of the mitochondrial Ca 2+ uniporter with SB‐202190 enhanced spontaneous sarcoplasmic reticulum Ca 2+ release and had no significant effect on arrhythmias in both WT and HIP rat hearts. Conclusions [Ca 2+ ] m is reduced in myocytes from rats with T2D due to a combination of exacerbated mitochondrial Ca 2+ extrusion through mitoNCX and impaired mitochondrial Ca 2+ uptake. Partial mitoNCX inhibition limits sarcoplasmic reticulum Ca 2+ leak and arrhythmias in T2D hearts, whereas mitochondrial Ca 2+ uniporter activation does not.