Aim: The role of the Na⁺/K⁺-ATPase (NKA) in heart failure associated with myocardial infarction (MI) is poorly understood. The elucidation of its precise function is hampered by the existence of two catalytic NKA isoforms (NKA-α1 and NKA-α2). Our aim was to analyze the effects of an increased NKA-α2 expression on functional deterioration and remodeling during long term MI treatment in mice and its impact on Ca²⁺ handling and inotropy of the failing heart. Methods and Results: Wild-type (WT) and NKA-α2 transgenic (TG) mice (TG-α2) with a cardiac-specific overexpression of NKA-α2 were subjected to MI injury for 8 weeks. As examined by echocardiography, gravimetry and histology, TG-α2 mice were protected from functional deterioration and adverse cardiac remodeling. Contractility and Ca²⁺ transients (Fura 2-AM) in cardiomyocytes from MI-treated TG-α2 animals showed reduced Ca²⁺ amplitudes during pacing or after caffeine application. Ca²⁺ efflux in cardiomyocytes from TG-α2 mice was accelerated, and diastolic Ca²⁺ levels decreased. Based on these alterations, sarcomeres exhibited an enhanced sensitization and thus increased contractility. After the acute stimulation with the β-adrenergic agonist isoproterenol (ISO), cardiomyocytes from MI-treated TG-α2 mice responded with increased sarcomere shortenings and Ca²⁺ peak amplitudes. This positive inotropic response was absent in cardiomyocytes from WT-MI animals. Conclusions: Cardiomyocytes with NKA-α2 as predominant isoform minimize Ca²⁺ cycling but respond to β-adrenergic stimulation more efficiently during chronic cardiac stress. These mechanisms might improve the β-adrenergic reserve and contribute to functional preservation in heart failure.

中文翻译：

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Na+/K+-ATPase 的 α2 异构体可防止心肌梗塞后的病理重塑和 β-肾上腺素能脱敏

目的：Na ⁺ /K ⁺ -ATPase (NKA) 在与心肌梗塞 (MI) 相关的心力衰竭中的作用知之甚少。由于存在两种催化 NKA 异构体（NKA-α1 和 NKA-α2），对其精确功能的阐明受到阻碍。我们的目的是分析NKA-α2表达增加对小鼠长期MI治疗期间功能恶化和重塑的影响及其对Ca ^{2+ 的}影响衰竭心脏的处理和正性肌力。方法和结果：具有心脏特异性过表达 NKA-α2 的野生型 (WT) 和 NKA-α2 转基因 (TG) 小鼠 (TG-α2) 经受 MI 损伤 8 周。通过超声心动图、重量测定和组织学检查，TG-α2 小鼠免受功能恶化和不良心脏重塑的影响。来自 MI 处理的 TG-α2 动物的心肌细胞的收缩力和 Ca ²⁺瞬变（Fura 2-AM）在起搏期间或应用咖啡因后显示出降低的 Ca ²⁺振幅。TG-α2小鼠心肌细胞Ca ²⁺外流加速，舒张Ca ²⁺水平下降。基于这些改变，肌节表现出增强的敏化，从而增加了收缩性。在用 β-肾上腺素能激动剂异丙肾上腺素 (ISO) 进行急性刺激后，来自 MI 处理的 TG-α2 小鼠的心肌细胞以增加的肌节缩短和 Ca ²⁺峰值幅度作出反应。来自 WT-MI 动物的心肌细胞中不存在这种正性肌力反应。结论：以 NKA-α2 作为主要同种型的心肌细胞使 Ca ²⁺循环最小化，但在慢性心脏应激期间更有效地响应 β-肾上腺素能刺激。这些机制可能会改善 β-肾上腺素能储备并有助于心力衰竭的功能保存。