Effect of Mitochondrial Ca²⁺ Uptake on Arrhythmogenesis in Right Ventricular Hypertrophy in Rats and Mice

In patients with pulmonary arterial hypertension, death due to ventricular arrhythmias accounts for 8-26% of total deaths, so in this study we investigated whether mitochondrial Ca²⁺uptake affects ventricular arrhythmias in right ventricular hypertrophy (RVH).

A total of 70 rats were subcutaneously injected with monocrotaline (MCT-rats) or solvent; 8 mice underwent pulmonary artery banding (PAB) surgery. At 4 weeks after MCU injection or PAB surgery, trabeculae were dissected from the RVs. Levels of mitochondrial Ca²⁺, cytoplasmic Ca²⁺, and reactive oxygen species (ROS) were measured using fluorescence dyes. Mitochondrial calcium uniporter (MCU) expression was measured by Western blotting. Ca²⁺waves and arrhythmias were induced by electrical stimulation (24℃). Both MCT-rats and PAB-mice showed RVH. Ru360, an MCU inhibitor, improved arrhythmias in trabeculae from severe RVH, whereas it worsened them in trabeculae from milder RVH in MCT-rats. Depending on the degree of RVH, Ru360 decreased rhod-2 fluorescence in both MCT-rats and PAB-mice, and decreased Ca²⁺wave velocity, the 2',7'-dichlorofluorescein fluorescence slope, and MitoSox Red fluorescence in the MCT-rats. MCU expression increased with the degree of RVH.

Inhibition of mitochondrial Ca²⁺uptake improved arrhythmias in severe RVH, but worsened them in milder RVH, due to differences in mitochondrial Ca²⁺uptake, ROS production, and MCU expression.