BACKGROUND PANX1 (pannexin 1), a ubiquitously expressed ATP release membrane channel, has been shown to play a role in inflammation, blood pressure regulation, and myocardial infarction. However, the possible role of PANX1 in cardiomyocytes in the progression of heart failure has not yet been investigated. METHOD We generated a novel mouse line with constitutive deletion of PANX1 in cardiomyocytes (Panx1MyHC6). RESULTS PANX1 deletion in cardiomyocytes had no effect on unstressed heart function but increased the glycolytic metabolism and resulting glycolytic ATP production, with a concurrent decrease in oxidative phosphorylation, both in vivo and in vitro. In vitro, treatment of H9c2 (H9c2 rat myoblast cell line) cardiomyocytes with isoproterenol led to PANX1-dependent release of ATP and Yo-Pro-1 uptake, as assessed by pharmacological blockade with spironolactone and siRNA-mediated knockdown of PANX1. To investigate nonischemic heart failure and the preceding cardiac hypertrophy, we administered isoproterenol, and we demonstrated that Panx1MyHC6 mice were protected from systolic and diastolic left ventricle volume increases as a result of cardiomyocyte hypertrophy. Moreover, we found that Panx1MyHC6 mice showed decreased isoproterenol-induced recruitment of immune cells (CD45+), particularly neutrophils (CD11b+ [integrin subunit alpha M], Ly6g+ [lymphocyte antigen 6 family member G]), to the myocardium. CONCLUSIONS Together, these data demonstrate that PANX1 deficiency in cardiomyocytes increases glycolytic metabolism and protects against cardiac hypertrophy in nonischemic heart failure at least in part by reducing immune cell recruitment. Our study implies PANX1 channel inhibition as a therapeutic approach to ameliorate cardiac dysfunction in patients with heart failure.

中文翻译：

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心肌细胞 PANX1 控制肥大中的糖酵解和中性粒细胞募集。


背景 PANX1（pannexin 1）是一种普遍表达的 ATP 释放膜通道，已被证明在炎症、血压调节和心肌梗塞中发挥作用。然而，心肌细胞中 PANX1 在心力衰竭进展中的可能作用尚未得到研究。方法 我们构建了心肌细胞中 PANX1 组成型缺失的新型小鼠品系 (Panx1MyHC6)。结果 心肌细胞中 PANX1 缺失对无应激心脏功能没有影响，但增加了糖酵解代谢并导致糖酵解 ATP 产生，同时体内和体外氧化磷酸化减少。在体外，用异丙肾上腺素处理 H9c2（H9c2 大鼠成肌细胞系）心肌细胞导致 PANX1 依赖性 ATP 释放和 Yo-Pro-1 摄取，通过螺内酯药理阻断和 siRNA 介导的 PANX1 敲低进行评估。为了研究非缺血性心力衰竭和先前的心脏肥大，我们给予异丙肾上腺素，并证明 Panx1MyHC6 小鼠不会因心肌细胞肥大而导致收缩期和舒张期左心室容积增加。此外，我们发现 Panx1MyHC6 小鼠表现出异丙肾上腺素诱导的免疫细胞 (CD45+)，特别是中性粒细胞（CD11b+ [整合素亚基 α M]、Ly6g+ [淋巴细胞抗原 6 家族成员 G]）向心肌的募集减少。结论 总之，这些数据表明，心肌细胞中 PANX1 缺乏会增加糖酵解代谢，并至少部分通过减少免疫细胞募集来防止非缺血性心力衰竭中的心脏肥大。我们的研究表明 PANX1 通道抑制可作为改善心力衰竭患者心功能障碍的治疗方法。