Abstract
Introduction: Acute myocardial infarction (AMI) is associated with lethal ventricular arrhythmias. One important mechanism for these arrhythmias is delayed afterdepolarizations resulting from Ca2+ overload in border zone. Mitochondria participated in Ca2+ homeostasis, and the mitochondrial Ca2+ uniporter (MCU) mediates mitochondrial Ca2+ entry. We tested whether mitochondrial Ca2+ flux played a role in ventricular arrhythmias during AMI. Methods: Hearts and ventricular cells were isolated from CD1 wild type (Wt) and MCU knock down (MCU+/-) mice. Whole cell current-clamp was employed to record action potentials (APs). Cytoplasmic Ca2+ and mitochondrial Ca2+ were sampled by loading Indo-1 AM and Rhod-2 AM (recorded synchronously with APs) respectively. Electric pacing was used to induce arrhythmia. MCU mRNA and protein expression were evaluated by Western blotting & Real-Time PCR. Optical mapping was used to detect arrhythmias in the intact heart. Results: In MCU+/− mice, the mRNA (from 1.00 ± 0.02 to 0.42 ± 0.03 ) and protein expression (from 0.73 ± 0.07 to 0.33 ± 0.04) of MCU was substantially reduced, with peak mitochondrial Ca2+ transients (F/Fo) prominently decreased from 0.21 ± 0.02 to 0.14 ± 0.03. Infarct size was similar in the two models: Wt (48% ± 4%) and MCU+/- (44% ± 2%) mice. Two of eight of Wt mice died suddenly within 1 h after AMI, but none of MCU+/- mice died suddenly in this period. Compare to the Wt mice, pacing induced significantly less ventricular arrhythmias in MCU+/- mice during the first stage of coronary artery ligation as VT/VF duration decreased from 0.38 ± 0.09 s in Wt mice to 0.12 ± 0.05 s in MCU+/- mice. Consistent with a role of mitochondria in ischemic ventricular rhythms, inhibition of mitochondrial NCX by CGP-37157 (i.p. 0.4mg/100g) in both Wt and MCU+/− mice could abolish ventricular arrhythmias evoked by electric pacing during AMI. Furthermore, VT/VF was detected only in Wt mice at infarction border zone by optical mapping experiment. Finally, after AMI, action potential durations were longer in Wt mouse hearts/cardiomyocytes than those in MCU+/- mouse hearts/cardiomyocytes. Conclusion: Our study suggest a role for mitochondrial Ca2+ handling in arrhythmic risk during AMI. Reducing mitochondrial Ca2+ cycling improved arrhythmic risk.
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