Stimulation of the mitochondrial calcium uniporter mitigates chronic heart failure-associated ventricular arrhythmia in mice

Abstract

Background: An aberrant increase in the diastolic calcium concentration ([Ca²⁺]_i) level is a hallmark of heart failure (HF) and the cause of delayed afterdepolarization and ventricular arrhythmia (VA). Although mitochondria play a role in regulating [Ca²⁺]_i, whether they can compensate for the [Ca²⁺]_i abnormality in ventricular myocytes is unknown.

Objective: The purpose of this study was to investigate whether enhanced Ca²⁺ uptake of mitochondria may compensate for an abnormal increase in the [Ca²⁺]_i of ventricular myocytes in HF to effectively mitigate VA.

Methods: We used a HF mouse model in which myocardial infarction was induced by permanent left anterior descending coronary artery ligation. The mitochondrial Ca²⁺ uniporter was stimulated by kaempferol. Ca²⁺ dynamics and membrane potential were measured using an epifluorescence microscope, a confocal microscope, and the perforated patch-clamp technique. VA was induced in Langendorff-perfused hearts, and hemodynamic parameters were measured using a microtip transducer catheter.

Results: Protein expression of the mitochondrial Ca²⁺ uniporter, as assessed by its subunit expression, did not change between HF and sham mice. Treatment of cardiomyocytes with kaempferol, isolated from HF mice 28 days after coronary ligation, reduced the appearance of aberrant diastolic [Ca²⁺]_i waves and sparks and spontaneous action potentials. Kaempferol effectively reduced VA occurring in Langendorff-perfused hearts. Intravenous administration of kaempferol did not markedly affect left ventricular hemodynamic parameters.

Conclusion: The effects of kaempferol in HF of mice implied that mitochondria may have the potential to compensate for abnormal [Ca²⁺]_i. Mechanisms involved in mitochondrial Ca²⁺ uptake may provide novel targets for treatment of HF-associated VA.

Keywords: Calcium waves; Delayed afterdepolarization; Heart failure; Mitochondrial calcium uniporter; Mitochondrial calcium uptake; Ventricular arrhythmia.