Kaempferol protects mitochondria and alleviates damages against endotheliotoxicity induced by doxorubicin
Kaempferol protects mitochondria and alleviates damages against endotheliotoxicity induced by doxorubicin
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山奈酚保护线粒体并减轻阿霉素引起的内皮毒性损伤
DOI：
10.1016/j.biopha.2020.110040
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发表时间：
2020
影响因子：
7.5
通讯作者：
Ming He
中科院分区：
文献类型：
--
作者：
Weiqi Wu;Bin Yang;Yang Qiao;Qing Zhou;Huan He;Ming He
山奈酚（Kae）是一种类黄酮，存在于水果和其他蔬菜中，具有多种生物活性。14-3-3蛋白对各类损伤组织和细胞均有保护作用。阿霉素（Dox）引起活性氧（ROS）的过量产生，从而诱导内皮毒性和心脏毒性。我们推测Kae可能通过调节14-3-3γ或相关通路来保护血管内皮免受Dox毒性。建立HUVECs dox毒性损伤模型。用许多生理、酶、细胞和分子生物学指标来评估Kae的效果。我们的研究结果表明，通过Kae降低dox诱导的HUVECs损伤，促进总蛋白14-3-3γ和线粒体Bcl-2的表达，使Bad磷酸化，提高细胞活力、NO含量、DDAHⅡ活性、p-eNOS/eNOS比值和MMP水平，维持NAD+/NADH和GSH/GSSG平衡，降低LDH和caspase-3活性、ADMA含量、ROS生成、mPTP开放和凋亡。pAD/14-3-3 - γ- shrna下调14-3-3 - γ表达或ABT-737抑制Bcl-2活性可消除Kae的作用。本研究表明，Kae通过调节14-3-3γ和ADMA/DDAHⅡ/eNOS/NO通路，抑制氧化应激，改善线粒体功能，保护血管内皮免受dox诱导的损伤。
Kaempferol (Kae), a flavonoid, has been found in fruits and other vegetables, possesses many biological activities. 14-3-3 protein exerts protection on various types of injured tissues and cells. Doxorubicin (Dox) causes excessive reactive oxygen species (ROS) generation, which induces endotheliotoxicity and cardiotoxicity. We hypothesized that Kae could protect vascular endothelium by regulating 14-3-3γ or related pathways against Dox toxicity. HUVECs were established Dox-toxic injury models. Kae’s effects were assessed with many physiological, enzymatic, cellular, and molecular biological indexes. Our results showed that Dox-induced damage in HUVECs were reduced through Kae to promote the expression of total protein 14-3-3γ and mitochondrial Bcl-2, phosphorylate Bad, increase cell viability, NO content, DDAHⅡactivity, p-eNOS/eNOS ratio, and MMP levels, maintained NAD+/NADH and GSH/GSSG balance, and decrease LDH and caspase-3 activities, ADMA content, ROS generation, mPTP openness, and apoptosis. Kae’s effects were abolished with pAD/14-3-3γ-shRNA downregulating 14-3-3γ expression, or ABT-737 inhibiting Bcl-2 activity. This study demonstrated that Kae protected the vascular endothelium against Dox-induced damage by regulating 14-3-3γ and ADMA/DDAHⅡ/eNOS/NO pathway, inhibiting oxidative stress, and improving mitochondrial function.