Tetramethylpyrazine Attenuates the Endotheliotoxicity and the Mitochondrial Dysfunction by Doxorubicin via 14-3-3γBcl-2
Joint Authors
He, Ming
He, Huan
Yin, Dong
Zhou, Qing
Qiao, Yang
Yang, Bin
Li, Hongwei
Chen, Shuping
Source
Oxidative Medicine and Cellular Longevity
Issue
Vol. 2019, Issue 2019 (31 Dec. 2019), pp.1-20, 20 p.
Publisher
Hindawi Publishing Corporation
Publication Date
2019-12-03
Country of Publication
Egypt
No. of Pages
20
Main Subjects
Abstract EN
Doxorubicin (Dox) with cardiotoxicity and endotheliotoxicity limits its clinical application for cancer.
The toxicitic mechanism involves excess ROS generation.
14-3-3s have the protective effects on various injured tissues and cells.
Tetramethylpyrazine (TMP) is an alkaloid extracted from the rhizome of Ligusticum wallichii and has multiple bioactivities.
We hypothesize that TMP has the protective effects on vascular endothelium by upregulating 14-3-3γ.
To test the hypothesis, Dox-induced endotheliotoxicity was used to establish vascular endothelium injury models in mice and human umbilical vein endothelial cells.
The effects of TMP were assessed by determining thoracic aortic strips’ endothelium-dependent dilation (EDD), as well as LDH, CK, caspase-3, SOD, CAT, GSH-Px activities and MDA level in serum, apoptotic rate, and histopathological changes of vascular tissue (in vivo).
Also, cell viability, LDH and caspase-3 activities, ROS generation, levels of NAD+/NADH and GSH/GSSG, MMP, mPTP opening, and apoptotic rate were evaluated (in vitro).
The expression of 14-3-3γ and Bcl-2, as well as phosphorylation of Bad (S112), were determined by Western blot.
Our results showed that Dox-induced injury to vascular endothelium was decreased by TMP via upregulating 14-3-3γ expression in total protein and Bcl-2 expression in mitochondria, activating Bad (S112) phosphorylation, maintaining EDD, reducing LDH, CK, and caspase-3 activities, thereby causing a reduction in apoptotic rate, and histopathological changes of vascular endothelium (in vivo).
Furthermore, TMP increased cell viability and MMP levels, maintained NAD+/NADH, GSH/GSSG balance, decreased LDH and caspase-3 activities, ROS generation, mPTP opening, and apoptotic rate (in vitro).
However, the protective effects to vascular endothelium of TMP were significantly canceled by pAD/14-3-3γ-shRNA, an adenovirus that caused knockdown 14-3-3γ expression, or ABT-737, a specific Bcl-2 inhibitor.
In conclusion, this study is the first to demonstrate that TMP protects the vascular endothelium against Dox-induced injury via upregulating 14-3-3γ expression, promoting translocation of Bcl-2 to the mitochondria, closing mPTP, maintaining MMP, inhibiting RIRR mechanism, suppressing oxidative stress, improving mitochondrial function, and alleviating Dox-induced endotheliotoxicity.
American Psychological Association (APA)
Yang, Bin& Li, Hongwei& Qiao, Yang& Zhou, Qing& Chen, Shuping& Yin, Dong…[et al.]. 2019. Tetramethylpyrazine Attenuates the Endotheliotoxicity and the Mitochondrial Dysfunction by Doxorubicin via 14-3-3γBcl-2. Oxidative Medicine and Cellular Longevity،Vol. 2019, no. 2019, pp.1-20.
https://search.emarefa.net/detail/BIM-1204314
Modern Language Association (MLA)
Yang, Bin…[et al.]. Tetramethylpyrazine Attenuates the Endotheliotoxicity and the Mitochondrial Dysfunction by Doxorubicin via 14-3-3γBcl-2. Oxidative Medicine and Cellular Longevity No. 2019 (2019), pp.1-20.
https://search.emarefa.net/detail/BIM-1204314
American Medical Association (AMA)
Yang, Bin& Li, Hongwei& Qiao, Yang& Zhou, Qing& Chen, Shuping& Yin, Dong…[et al.]. Tetramethylpyrazine Attenuates the Endotheliotoxicity and the Mitochondrial Dysfunction by Doxorubicin via 14-3-3γBcl-2. Oxidative Medicine and Cellular Longevity. 2019. Vol. 2019, no. 2019, pp.1-20.
https://search.emarefa.net/detail/BIM-1204314
Data Type
Journal Articles
Language
English
Notes
Includes bibliographical references
Record ID
BIM-1204314