■PANX1(pannexin1),广泛表达的ATP释放膜通道,已经被证明在炎症中起作用,血压调节,和心肌梗塞。然而,尚未研究PANX1在心肌细胞中在心力衰竭进展中的可能作用.
■我们产生了一种在心肌细胞中具有PANX1组成性缺失的新型小鼠品系(Panx1MyHC6)。
■心肌细胞中的PANX1缺失对无压力的心脏功能没有影响,但增加了糖酵解代谢并导致糖酵解ATP的产生,同时减少氧化磷酸化,体内和体外。体外,用异丙肾上腺素治疗H9c2心肌细胞导致PANX1依赖性释放ATP和Yo-Pro-1摄取,通过螺内酯和siRNA介导的PANX1敲低的药物阻断评估。为了研究非缺血性心力衰竭和先前的心脏肥大,我们服用了异丙肾上腺素,我们证明,Panx1MyHC6小鼠受到保护,不会因心肌细胞肥大而导致左心室收缩和舒张体积增加。此外,我们发现,Panx1MyHC6小鼠显示减少异丙肾上腺素诱导的免疫细胞募集(CD45+),特别是中性粒细胞(CD11b+,Ly6g+),心肌。
■一起,这些数据表明,在非缺血性心力衰竭中,PANX1缺乏可增加糖酵解代谢,并至少部分通过减少免疫细胞募集来防止心肌肥大.我们的研究表明,抑制PANX1通道可作为改善心力衰竭患者心功能不全的治疗方法。
UNASSIGNED: 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.
UNASSIGNED: We generated a novel mouse line with constitutive deletion of PANX1 in cardiomyocytes (Panx1MyHC6).
UNASSIGNED: 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 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+, Ly6g+), to the myocardium.
UNASSIGNED: 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.