Life sciences · 2025
Metformin alleviates hyperkalemia-induced arrhythmia and cardiac injury in mice through decreasing SK2 and intracellular Ca2.
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Cui Jie, Adu-Amankwaah Joseph, Song Hequn, Wang Ruixin, Song Nina, Liu Kuntao, Yang Dongqi, Du Mingjia, Kong Delong, Wang Shijun, Mi Shouling, Tan Rubin
Аннотация
BACKGROUND: Hyperkalemia is a critical electrolyte imbalance that can lead to life-threatening arrhythmia and cardiac injury. The potential protective role of metformin on acute hyperkalemia remains unclear. Our study aimed to investigate the mechanisms of metformin against hyperkalemia-induced arrhythmia and cardiac injury.
METHODS: We established hyperkalemia-induced arrhythmia model in vivo using intragastric KCl overload in mice, and followed by low- or high-dose metformin or insulin to evaluate cardiac electrocardiography (ECG), cardiac injury, and the regulation of key potassium channels. Additionally, we cultured HL-1 cells under varying potassium concentration, followed by treatment with insulin or metformin to assess the cell viability, apoptosis, the regulation of key potassium channels and intracellular and extracellular calcium (Ca2+) dynamics.
KEY FINDINGS: Our study demonstrates that both metformin and insulin have protective effects against hyperkalemia-induced arrhythmia. Notably, metformin significantly reversed the expression of Kv4.2 and SK2 channels, which are critical for maintaining normal cardiac electrical activity. Furthermore, metformin improved cardiomyocyte viability and reduced apoptosis in hyperkalemic conditions. Our findings also reveal that metformin increased serum Ca2+ levels and reduced intracellular Ca2+ levels, which is associated with the upregulation of parathyroid hormone (PTH). These results suggest that metformin exerts its protective effects through distinct mechanisms compared to insulin.
SIGNIFICANCE: These findings have important implications for the management of hyperkalemia, particularly in patients with underlying insulin resistance or those who cannot tolerate insulin therapy. By demonstrating the protective effects of metformin, our study opens new avenues for therapeutic intervention and further research into the role of metformin in cardiac protection.
METHODS: We established hyperkalemia-induced arrhythmia model in vivo using intragastric KCl overload in mice, and followed by low- or high-dose metformin or insulin to evaluate cardiac electrocardiography (ECG), cardiac injury, and the regulation of key potassium channels. Additionally, we cultured HL-1 cells under varying potassium concentration, followed by treatment with insulin or metformin to assess the cell viability, apoptosis, the regulation of key potassium channels and intracellular and extracellular calcium (Ca2+) dynamics.
KEY FINDINGS: Our study demonstrates that both metformin and insulin have protective effects against hyperkalemia-induced arrhythmia. Notably, metformin significantly reversed the expression of Kv4.2 and SK2 channels, which are critical for maintaining normal cardiac electrical activity. Furthermore, metformin improved cardiomyocyte viability and reduced apoptosis in hyperkalemic conditions. Our findings also reveal that metformin increased serum Ca2+ levels and reduced intracellular Ca2+ levels, which is associated with the upregulation of parathyroid hormone (PTH). These results suggest that metformin exerts its protective effects through distinct mechanisms compared to insulin.
SIGNIFICANCE: These findings have important implications for the management of hyperkalemia, particularly in patients with underlying insulin resistance or those who cannot tolerate insulin therapy. By demonstrating the protective effects of metformin, our study opens new avenues for therapeutic intervention and further research into the role of metformin in cardiac protection.