Kaempferol protects mitochondria and alleviates damages against endotheliotoxicity induced by doxorubicin - 19/04/20
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Graphical abstract |
Kaempferol protected vascular endothelium against doxorubicin-induced endotheliotoxicity via upregulating 14-3-3γ, inhibiting RIRR mechanism, regulating ADMA/DDAHⅡ/eNOS/ NO pathway, improving mitochondrial function.
Highlights |
• | Kaempferol (Kae) protects HUVECs against doxorubicin-induced endotheliotoxicity. |
• | Mechanism of Kae is associated with 14-3-3γ/Bcl-2 and ADMA/DDAH Ⅱ/eNOS/NO pathway. |
• | Mitochondria are the target organelles of Kae’s protection. |
Abstract |
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.
Le texte complet de cet article est disponible en PDF.Abbreviations : ADMA, Atr, cyt C, CsA, DDAH, Dox, ECAR, eNOS, FBS, GSH, GSSG, HPLC, HUVECs, Kae, L-Arg, LDH, MMP, mPTP, NAD+, NO, OCR, RIRR, ROS
Keywords : Kaempferol, Doxorubicin, Endotheliotoxicity, Mitochondria, 14-3-3γ/Bcl-2
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Vol 126
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