Department of Pharmacy, the 940th Hospital of Joint Logistics Support force of PLA, Lanzhou, Gansu 730050, PR China.
Department of Chemistry, School of Pharmacy, Fourth Military Medical University, XiAn, Shaanxi 710032, PR China.
Life Sci. 2020 May 1;248:116481. doi: 10.1016/j.lfs.2019.05.037. Epub 2019 May 15.
Hypobaric hypoxia (HH), linked to oxidative stress, impairs cardiac function. We synthesized a novel nitronyl nitroxide radical, an HPN derivative (HEPN) and investigated the protective effects of HEPN and HPN against HH-induced heart injury in mice and the underlying mechanisms of action.
Mice were administered with HPN (200 mg/kg) or HEPN (200 mg/kg) 30 min before exposed to HH. The cardiac function was measured. Serum AST, CK, LDH and cTnI were estimated. Heart tissue oxidase activity, SOD, CAT, GSH-Px, ROS and MDA were estimated. ATP content, Na/K-ATPase and Ca/Mg-ATPase activity was measured. The expression of HIF-1, VEGF, Nrf2, HO-1, Bax, Bcl-2, Caspase-3 was estimated.
Results showed that pretreatment with HEPN or HPN led to a dramatic decrease in the activity of biochemical markers AST, CK, LDH and cTnI in murine serum. They increased the activity of SOD, CAT and GSH-Px and reduced the level of ROS and MDA in the hearts of mice. HEPN and HPN could increase the expression of Nrf2 and OH-1. They could maintain the ATPase activity. The Bax and Caspase-3 expression as well as the ratio of Bax/Bcl-2 were significantly downregulated and the Bcl-2 expression was upregulated by HPN or HEPN compared to the HH group. They may attenuate the HH-induced oxidant stress via free radical scavenging activity.
The present study showed that the nitronyl nitroxide radical HEPN and HPN may be potential therapeutic agents for treatment of HH-induced cardiac dysfunction.
低气压缺氧（HH）与氧化应激有关，可损害心脏功能。我们合成了一种新型的硝酰氮自由基，HPN 的衍生物（HEPN），并研究了 HEPN 和 HPN 对小鼠 HH 诱导的心脏损伤的保护作用及其作用机制。
小鼠在暴露于 HH 之前 30 分钟给予 HPN（200mg/kg）或 HEPN（200mg/kg）。测量心脏功能。测定血清 AST、CK、LDH 和 cTnI。测定心肌氧化酶活性、SOD、CAT、GSH-Px、ROS 和 MDA。测定 ATP 含量、Na/K-ATPase 和 Ca/Mg-ATPase 活性。测定 HIF-1、VEGF、Nrf2、HO-1、Bax、Bcl-2、Caspase-3 的表达。
结果表明，HEPN 或 HPN 预处理可显著降低小鼠血清中 AST、CK、LDH 和 cTnI 等生化标志物的活性。它们提高了 SOD、CAT 和 GSH-Px 的活性，降低了小鼠心脏中 ROS 和 MDA 的水平。HEPN 和 HPN 可以增加 Nrf2 和 OH-1 的表达。它们可以维持 ATP 酶的活性。与 HH 组相比，Bax 和 Caspase-3 的表达以及 Bax/Bcl-2 的比值明显下调，Bcl-2 的表达上调。它们可能通过清除自由基活性来减轻 HH 引起的氧化应激。
本研究表明，硝酰氮自由基 HEPN 和 HPN 可能是治疗 HH 诱导的心脏功能障碍的潜在治疗药物。
