Systemic hypoxia is a common element in most perinatal emergencies and is a known driver of Bnip3 expression in the neonatal heart. Bnip3 plays a prominent role in the evolution of necrotic cell death, disrupting ER calcium homeostasis and initiating mitochondrial permeability transition (MPT). Emerging evidence suggests a cardioprotective role for the prostaglandin E1 analogue misoprostol during periods of hypoxia, but the mechanisms for this protection are not completely understood. Using a combination of mouse and cell models, we tested if misoprostol is cardioprotective during neonatal hypoxic injury by altering Bnip3 function. Here we report that hypoxia elicits mitochondrial-fragmentation, MPT, reduced ejection fraction, and evidence of necroinflammation, which were abrogated with misoprostol treatment or Bnip3 knockout. Through molecular studies we show that misoprostol leads to PKA-dependent Bnip3 phosphorylation at threonine-181, and subsequent redistribution of Bnip3 from mitochondrial Opa1 and the ER through an interaction with 14-3-3 proteins. Taken together, our results demonstrate a role for Bnip3 phosphorylation in the regulation of cardiomyocyte contractile/metabolic dysfunction, and necroinflammation. Furthermore, we identify a potential pharmacological mechanism to prevent neonatal hypoxic injury.

中文翻译：

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米索前列醇治疗可通过Bnip3上的14-3-3和PKA调节基序防止低氧诱导的心脏功能障碍

系统性缺氧是大多数围产期紧急情况中的常见因素，并且是新生儿心脏中Bnip3表达的已知驱动因素。Bnip3在坏死细胞死亡的演变，破坏ER钙稳态和启动线粒体通透性转变（MPT）中起着重要作用。越来越多的证据表明，在缺氧期间，前列腺素E1类似物米索前列醇具有心脏保护作用，但这种保护机制尚不完全清楚。使用小鼠和细胞模型的组合，我们通过改变Bnip3功能测试了米索前列醇在新生儿缺氧性损伤期间是否具有心脏保护作用。在这里我们报道缺氧引起线粒体碎片，MPT，射血分数降低和坏死性炎症的证据，这被米索前列醇治疗或Bnip3敲除所废除。通过分子研究，我们发现米索前列醇导致PKA依赖的Bnip3在苏氨酸181磷酸化，并随后通过与14-3-3蛋白相互作用从线粒体Opa1和ER重新分配Bnip3。两者合计，我们的结果表明Bnip3磷酸化在调节心肌细胞收缩/代谢功能障碍和坏死性炎症中的作用。此外，我们确定了预防新生儿缺氧性损伤的潜在药理机制。和坏死性炎症。此外，我们确定了预防新生儿缺氧性损伤的潜在药理机制。和坏死性炎症。此外，我们确定了预防新生儿缺氧性损伤的潜在药理机制。