Cardiovascular disease is the leading cause of death worldwide. Cardiac electrical remodeling including altered ion channel expression and imbalance of calcium homeostasis can have detrimental effects on cardiac function. While it has been extensively reported that miR-221/222 are involved in structural remodeling, their role in electrical remodeling still has to be evaluated. We previously reported that subunits of the L-type Ca2+ channel (LTCC) are direct targets of miR-221/222. Furthermore, HL-1 cells transfected with miR-221 or -222 mimics showed a reduction in LTCC current density while the voltage-dependence of activation was not altered. The aim of the present study was to determine the influence of miR-221/222 on cardiomyocyte calcium handling and function. Transient transfection of HL-1 cells with miR-221/222 mimics led to slower depolarization-dependent Ca2+ entry and increased proportion of non-responding cells. Angiotensin II-induced Ca2+ release from the SR was not affected by miR-221/222. In miR-222-transfected neonatal cardiomyocytes the isoprenaline-induced positive inotropic effect on the intracellular Ca2+ transient was lost and the positive chronotropic effect on spontaneous beating activity was strongly reduced. This could have severe consequences for cardiomyocytes and could lead to a reduced contractility and systolic dysfunction of the whole heart. This study adds a new role of miR-221/222 in cardiomyocytes by showing the impact on β-adrenergic regulation of LTCC function, calcium handling and beating frequency. Together with the previous report that miR-221/222 reduce GIRK1/4 function and LTCC current density, it expands our knowledge about the role of these miRs on cardiac ion channel regulation.

中文翻译：

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miR-221/222对心肌细胞钙离子处理和功能的影响

心血管疾病是全世界死亡的主要原因。包括离子通道表达改变和钙稳态失衡在内的心脏电重构会对心脏功能产生不利影响。虽然已经广泛报道 miR-221/222 参与结构重塑，但它们在电重塑中的作用仍有待评估。我们之前报道过 L 型 Ca2+ 通道 (LTCC) 的亚基是 miR-221/222 的直接靶标。此外，用 miR-221 或 -222 模拟物转染的 HL-1 细胞显示出 LTCC 电流密度降低，而激活的电压依赖性没有改变。本研究的目的是确定 miR-221/222 对心肌细胞钙处理和功能的影响。用 miR-221/222 模拟物瞬时转染 HL-1 细胞导致去极化依赖性 Ca2+ 进入速度变慢，无反应细胞的比例增加。血管紧张素 II 诱导的 Ca2+ 从 SR 释放不受 miR-221/222 的影响。在转染 miR-222 的新生儿心肌细胞中，异丙肾上腺素诱导的对细胞内 Ca2+ 瞬变的正性肌力作用丧失，对自发搏动活动的正性变时作用显着降低。这可能对心肌细胞产生严重后果，并可能导致整个心脏收缩力下降和收缩功能障碍。该研究通过显示对 LTCC 功能、钙处理和搏动频率的 β-肾上腺素能调节的影响，增加了 miR-221/222 在心肌细胞中的新作用。