Atorvastatin attenuates ferroptosis-dependent myocardial injury and inflammation following coronary microembolization via the Hif1a/Ptgs2 pathway.
Atorvastatin attenuates ferroptosis-dependent myocardial injury and inflammation following coronary microembolization via the Hif1a/Ptgs2 pathway.
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DOI：
10.3389/fphar.2022.1057583
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发表时间：
2022
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
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目的：冠状动脉微栓塞（CME）是经皮冠状动脉介入术后严重的围手术期并发症。铁下垂已在多种心血管疾病中发现。在本研究中，我们旨在探讨阿托伐他汀（ATV）对CME后铁下垂和炎症的影响，并阐明其潜在机制。方法：采用左心室注射微球法建立大鼠CME模型。去铁胺（DFO），一种选择性铁下垂抑制剂，或ATV在建模前预处理。检测心功能及心肌肌钙蛋白T （cTnT）水平。测定铁下垂相关基因、丙二醛（MDA）、谷胱甘肽（GSH）和亚铁（Fe2+）水平以验证铁下垂。检测肿瘤坏死因子α (TNF-α)和白细胞介素1β (IL-1β)水平，判断炎症程度。染色质免疫沉淀法测定缺氧诱导因子1亚单位α (Hif1a)与前列腺素内过氧化物合酶-2 （Ptgs2）启动子的结合。结果：CME诱导铁下垂和炎症，MDA（~ 2.5倍，p < 0.01）、Fe2+（~ 1.5倍，p < 0.01）、TNF-α和IL-1β水平升高，GSH水平降低（~ 42%,p < 0.01）。同时，Ptgs2水平显著升高，谷胱甘肽过氧化物酶4 （Gpx4）和溶质载体家族7成员11 （Slc7a11）水平降低。cTnT水平升高7倍（p < 0.01）。左心室射血分数（LVEF）显著降低（假手术组为~ 85%，CME组为~ 45%，p < 0.01）。DFO或Ptgs2沉默抑制MDA、Ptgs2、TNF-α和IL-1β的增加，诱导GSH和Gpx4水平，随后cTnT水平降低约50% （p < 0.01）。LVEF改善约2倍（p < 0.01）。从机制上讲，转录因子Hif1a结合Ptgs2的启动子并上调其表达。此外，ATV抑制Hif1a/Ptgs2轴的激活，减轻心肌铁下垂和炎症，从而改善cme诱导的心肌损伤（LVEF，升高~ 34%；cTnT，降低~ 1.8倍，p < 0.01）。结论：阿托伐他汀通过Hif1a/Ptgs2途径改善CME后铁中毒介导的心肌损伤和炎症。
Objectives: Coronary microembolization (CME) represents a serious periprocedural complication after percutaneous coronary intervention. Ferroptosis has been identified in multiple cardiovascular diseases. In this study, we aimed to investigate the effects of atorvastatin (ATV) on ferroptosis and inflammation following CME and elucidate the underlying mechanism. Methods: We established a rat model of CME by injecting microspheres into the left ventricle. Deferoxamine (DFO), a selective ferroptosis inhibitor, or ATV was pretreated before modeling. Cardiac function and cardiac troponin T (cTnT) levels were detected. Levels of ferroptosis-associated genes, malondialdehyde (MDA), glutathione (GSH), and ferrous iron (Fe2+) were measured to validate ferroptosis. Levels of tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) were assayed to determine the inflammation. Chromatin immunoprecipitation was performed to determine the binding of hypoxia-inducible factor 1 subunit alpha (Hif1a) to the promoter of prostaglandin-endoperoxide synthase-2 (Ptgs2). Results: Ferroptosis and inflammation were induced following CME with increased levels of MDA (∼2.5 fold, p < 0.01), Fe2+ (∼1.5 fold, p < 0.01), TNF-α, and IL-1β and decreased GSH levels (∼42%, p < 0.01). Meanwhile, the level of Ptgs2 was significantly increased, while those of glutathione peroxidase 4 (Gpx4) and solute carrier family 7 member 11 (Slc7a11) were decreased. The level of cTnT was increased by 7-fold (p < 0.01). Left ventricular ejection fraction (LVEF) was significantly reduced (∼85% in the sham group versus ∼45% in the CME group, p < 0.01). DFO or Ptgs2 silencing inhibited the increase of MDA, Ptgs2, TNF-α, and IL-1β, and induced the levels of GSH and Gpx4, followed by reduction in cTnT levels by approximately 50% (p < 0.01). LVEF was improved by approximately 2 fold (p < 0.01). Mechanistically, the transcription factor Hif1a bound to the promoter of Ptgs2 and upregulated its expression. In addition, ATV inhibited the activation of the Hif1a/Ptgs2 axis and attenuated cardiac ferroptosis and inflammation, thus ameliorating CME-induced myocardial injury (LVEF, ∼34% elevation; cTnT, ∼1.8 fold decrease, p < 0.01). Conclusion: Atorvastatin ameliorates ferroptosis-mediated myocardial injury and inflammation following CME via the Hif1a/Ptgs2 pathway.
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影响因子：
32.4
作者：
Palazon, Asis;Goldrath, Ananda W.;Nizet, Victor;Johnson, Randall S.
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作者：
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DOI：
10.1016/j.bbrc.2021.08.017
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2.6
作者：
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