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Published on: May 27, 2010
Stimulation of the mitochondrial calcium uniporter mitigates chronic heart failure-associated ventricular arrhythmia
Hikaru Hagiwara1, Masaya Watanabe1, Yoichiro Fujioka2
1Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
Insights
Mitochondria may compensate for abnormal calcium levels in heart failure (HF) to reduce ventricular arrhythmias (VA). Stimulating mitochondrial calcium uptake with kaempferol mitigated VA in HF mice, suggesting new therapeutic targets.
Area of Science:
- Cardiology
- Mitochondrial Physiology
- Calcium Signaling
Background:
- Aberrant diastolic calcium concentration ([Ca2+]i) is a hallmark of heart failure (HF).
- This calcium abnormality contributes to delayed afterdepolarizations and ventricular arrhythmias (VA).
- The role of mitochondria in compensating for [Ca2+]i dysregulation in HF remains unclear.
Purpose of the Study:
- To investigate if enhanced mitochondrial calcium uptake can mitigate ventricular arrhythmias in heart failure.
- To determine if mitochondria can compensate for abnormal intracellular calcium in ventricular myocytes during HF.
Main Methods:
- Utilized a HF mouse model induced by coronary artery ligation.
- Stimulated the mitochondrial Ca2+ uniporter using kaempferol.
- Measured Ca2+ dynamics, membrane potential, induced VA, and hemodynamic parameters.
Main Results:
- Kaempferol treatment reduced aberrant diastolic [Ca2+]i waves, sparks, and spontaneous action potentials in HF cardiomyocytes.
- Kaempferol effectively reduced ventricular arrhythmias in Langendorff-perfused HF hearts.
- No significant change in mitochondrial Ca2+ uniporter expression was observed between HF and sham mice.
Conclusions:
- Mitochondria show potential to compensate for abnormal intracellular calcium in HF.
- Targeting mitochondrial calcium uptake mechanisms may offer novel therapeutic strategies for HF-associated VA.
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.
