The Calcilytic Drug Calhex-231 Ameliorates Vascular Hyporesponsiveness in Traumatic Hemorrhagic Shock by Inhibiting Oxidative Stress and miR-208a-Mediated Mitochondrial Fission.
The Calcilytic Drug Calhex-231 Ameliorates Vascular Hyporesponsiveness in Traumatic Hemorrhagic Shock by Inhibiting Oxidative Stress and miR-208a-Mediated Mitochondrial Fission.
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溶钙药物 Calhex-231 通过抑制氧化应激和 miR-208a 介导的线粒体裂变改善创伤性失血性休克中的血管反应低下
DOI：
10.1155/2020/4132785
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发表时间：
2020
影响因子：
--
通讯作者：
Yang G
中科院分区：
文献类型：
--
作者：
Lei Y;Peng X;Hu Y;Xue M;Li T;Liu L;Yang G
钙敏感受体（CaSR）在人类细胞外钙稳态中发挥着重要作用。令人惊讶的是，CaSR 也在非稳态组织中表达，并参与调节多种细胞功能。本研究的目的是确定 CaSR 负调节剂 Calhex-231 (Cal) 是否可能通过改善心血管功能有益于治疗创伤性失血性休克 (THS)，并研究其机制。 本研究使用经过 THS 和缺氧处理的血管平滑肌细胞 (VSMC) 的大鼠。研究了钙对 THS 大鼠心血管功能、动物存活、血流动力学和重要器官功能的影响，以及与氧化应激、线粒体融合裂变和 microRNA (miR-208a) 的关系。 Cal 显着改善血流动力学、升高血压、增加重要器官血液灌注和局部供氧，并显着改善 THS 大鼠的生存结果。此外，Cal 在体内和体外显着改善了 THS 后的血管反应性。 Cal 还恢复了 THS 诱导的肌球蛋白轻链 (MLC) 磷酸化（VSMC 收缩的关键要素）的减少。 MLC 磷酸化的抑制会拮抗 THS 后钙诱导的血管反应性恢复。 Cal 抑制 THS 大鼠和缺氧 VSMC 的氧化应激。同时，THS诱导血管组织中线粒体裂变蛋白Drp1和Fis1的表达，并降低线粒体融合蛋白Mfn1的表达。 Cal 降低了 Drp1 和 Fis1 的表达。在缺氧的 VSMC 中，Cal 抑制线粒体断裂并保留线粒体形态。此外，miR-208a 模拟物降低 Fis1 表达，而 miR-208a 抑制剂可阻止缺氧 VSMC 中 Cal 诱导的 Fis1 下调。 Calhex-231 在有效治疗创伤性失血性休克方面表现出突出的潜力，其有益效果来自于它通过抑制氧化应激和 miR-208a 介导的线粒体裂变来保护血管功能。
The calcium-sensing receptor (CaSR) plays a fundamental role in extracellular calcium homeostasis in humans. Surprisingly, CaSR is also expressed in nonhomeostatic tissues and is involved in regulating diverse cellular functions. The objective of this study was to determine if Calhex-231 (Cal), a negative modulator of CaSR, may be beneficial in the treatment of traumatic hemorrhagic shock (THS) by improving cardiovascular function and investigated the mechanisms. Rats that had been subjected to THS and hypoxia-treated vascular smooth muscle cells (VSMCs) were used in this study. The effects of Cal on cardiovascular function, animal survival, hemodynamics, and vital organ function in THS rats and the relationship to oxidative stress, mitochondrial fusion-fission, and microRNA (miR-208a) were investigated. Cal significantly improved hemodynamics, elevated blood pressure, increased vital organ blood perfusion and local oxygen supply, and markedly improved the survival outcomes of THS rats. Furthermore, Cal significantly improved vascular reactivity after THS in vivo and in vitro. Cal also restored the THS-induced decrease in myosin light chain (MLC) phosphorylation (the key element for VSMC contraction). Inhibition of MLC phosphorylation antagonized the Cal-induced restoration of vascular reactivity following THS. Cal suppressed oxidative stress in THS rats and hypoxic-VSMCs. Meanwhile, THS induced expression of mitochondrial fission proteins Drp1 and Fis1 and decreased expression of mitochondrial fusion protein Mfn1 in vascular tissues. Cal reduced expression of Drp1 and Fis1. In hypoxic-VSMCs, Cal inhibited mitochondrial fragmentation and preserved mitochondrial morphology. In addition, miR-208a mimic decreased Fis1 expression, and miR-208a inhibitor prevented Cal-induced Fis1 downregulation in hypoxic-VSMCs. Calhex-231 exhibits outstanding potential for effective therapy of traumatic hemorrhagic shock, and the beneficial effects result from its protection of vascular function via inhibition of oxidative stress and miR-208a-mediated mitochondrial fission.
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DOI：
10.3390/antiox7010013
发表时间：
2018-01-16
期刊：
Antioxidants (Basel, Switzerland)
影响因子：
--
作者：
Ježek J;Cooper KF;Strich R
通讯作者：
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8.8
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10.1124/jpet.107.123901
发表时间：
2007-10-01
影响因子：
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作者：
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DOI：
10.1186/s13054-018-1967-3
发表时间：
2018-02-27
期刊：
Critical care (London, England)
影响因子：
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作者：
Levy B;Fritz C;Tahon E;Jacquot A;Auchet T;Kimmoun A
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Kimmoun A