5-Methoxytryptophan attenuates postinfarct cardiac injury by controlling oxidative stress and immune activation
5-Methoxytryptophan attenuates postinfarct cardiac injury by controlling oxidative stress and immune activation
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DOI：
10.1016/j.yjmcc.2021.05.014
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发表时间：
2021-06-05
影响因子：
5
通讯作者：
Lee, Chii-Ming
中科院分区：
文献类型：
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作者：
Hsu, Wan-Tseng;Tseng, Ya-Hsuan;Lee, Chii-Ming
目的：心肌梗死（MI）仍然是心力衰竭的主要原因。5-5-甲氧基色氨酸（5-MTP）是L-色氨酸的5-甲氧基吲哚代谢产物，具有抗炎和抗纤维化作用，但MI损害心脏5-MTP的生物合成。因此，我们评估了外源性5-MTP给药对挽救MI后心脏损伤的作用。方法与结果：在对5-MTP进行详细的药代动力学分析后，在MI后0.5和24 h，对已进行左前降支冠状动脉结扎的Sprague道利大鼠腹腔内给予17 mg/kg 5-MTP或生理盐水。分别用超声心动图、氯化三苯基四氮唑染色和Masson三色染色评价心脏收缩功能、梗死面积和纤维化。通过caspase-3和心肌肌钙蛋白I染色分析心肌细胞凋亡。5-MTP治疗减少了梗死面积和心肌细胞凋亡;减轻了收缩功能障碍和左心室扩张;并减少了心肌细胞肥大、心肌纤维化和梗死范围扩大。重要的是，5-MTP通过保护线粒体抗氧化酶和下调活性氧生成NADPH氧化酶亚型和内皮素-1来减轻氧化应激。因此，5-MTP处理的MI大鼠心脏表现出较低水平的趋化因子和细胞因子，即白细胞介素（IL）-1 β、IL-18、IL-6、C-C基序趋化因子配体（CCL）-2和CCL 5，同时伴有CD 11b+细胞和CD 4 + T细胞浸润减少。值得注意的是，5-MTP对H2 O2诱导的HL-1心肌细胞和人脐静脉内皮细胞损伤的保护作用。结论：5-MTP通过促进线粒体稳定和控制氧化还原失衡来预防MI后心脏损伤。这种细胞保护作用改善了巨噬细胞和T细胞浸润，从而减少了梗死面积，减轻了纤维化，并恢复了心肌功能。
Aims: Myocardial infarction (MI) remains a major cause of heart failure. 5-Methoxytryptophan (5-MTP), a 5methoxyindole metabolite of L-tryptophan, exerts anti-inflammatory and antifibrotic effects, but MI impairs the biosynthesis of cardiac 5-MTP. Therefore, we evaluated the effect of exogenous 5-MTP administration on rescuing post-MI cardiac injury. Methods and results: After a detailed pharmacokinetic analysis of 5-MTP, Sprague Dawley rats that had undergone left anterior descending coronary artery ligation received intraperitoneal administration of either 17 mg/kg 5MTP or saline at 0.5 and 24 h after MI. Cardiac systolic function, infarction size, and fibrosis were evaluated using echocardiography, triphenyltetrazolium chloride staining, and Masson trichrome staining, respectively. Myocardial apoptosis was analyzed by staining for caspase-3 and cardiac troponin I. 5-MTP treatment decreased the infarct area and myocardial apoptosis; attenuated systolic dysfunction and left ventricular dilatation; and reduced cardiomyocyte hypertrophy, myocardial fibrosis, and infarct expansion. Crucially, 5-MTP alleviated oxidative stress by preserving mitochondrial antioxidant enzymes and downregulating reactive oxygen species-generating NADPH oxidase isoforms and endothelin-1. Consequently, 5-MTP-treated MI rat hearts exhibited lower levels of chemokines and cytokines, namely interleukin (IL)-1 beta, IL-18, IL-6, C-C motif chemokine ligand (CCL)-2, and CCL5, accompanied by reduced infiltration of CD11b+ cells and CD4+ T cells. Notably, 5-MTP protected against H2O2-induced damage in HL-1 cardiomyocytes and human umbilical vein endothelial cells in vitro. Conclusion: 5-MTP prevented post-MI cardiac injury by promoting mitochondrial stabilization and controlling redox imbalance. This cytoprotective effect ameliorated macrophage and T-cell infiltration, thus reducing the infarct size, attenuating fibrosis, and restoring myocardial function.