Targeting glutathione with the triterpenoid CDDO-Im protects against benzo-a-pyrene-1,6-quinone-induced cytotoxicity in
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Targeting glutathione with the triterpenoid CDDO‑Im protects against benzo‑a‑pyrene‑1,6‑quinone‑induced cytotoxicity in endothelial cells Halley Shukla1 · Ho Young Lee1 · Ashkon Koucheki1 · Humaira A. Bibi1 · Gabriella Gaje1 · Xiaolun Sun2 · Hong Zhu3 · Y. Robert Li3 · Zhenquan Jia1 Received: 27 February 2020 / Accepted: 11 July 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Epidemiological studies have exhibited a strong correlation between exposure to air pollution and deaths due to vascular diseases such as atherosclerosis. Benzo-a-pyrene-1,6-quinone (BP-1,6-Q) is one of the components of air p ollution. This study was to examine the role of GSH in BP-1,6-Q mediated cytotoxicity in human EA.hy96 endothelial cells and demonstrated that induction of cellular glutathione by a potent triterpenoid, CDDO-Im (1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl] imidazole), protects cells against BP-1,6-Q induced protein and lipid damage. Incubation of EA.hy926 endothelial cells with BP-1,6-Q caused a significant increase in dose-dependent cytotoxicity as measured by LDH release assay and both apoptotic and necrotic cell deaths as measured by flow cytometric analysis. Incubation of EA.hy926 endothelial cells with BP-1,6-Q also caused a significant decrease in cellular GSH levels. The diminishment of cellular GSH by buthionine sulfoximine (BSO) potentiated BP-1,6-Q-induced toxicity significantly suggesting a critical involvement of GSH in BP-1,6-Q induced cellular toxicity. GSH-induction by CDDO-Im significantly protects cells against BP-1,6-Q induced protein and lipid damage as measured by protein carbonyl (PC) assay and thiobarbituric acid reactive substances (TBARS) assay, respectively. However, the co-treatment of cells with CDDO-Im and BSO reversed the cytoprotective effect of CDDO-Im on BP-1,6-Q-mediated lipid peroxidation and protein oxidation. These results suggest that induction of GSH by CDDO-Im might be the important cellular defense against BP-1,6-Q induced protein and lipid damage. These findings would contribute to better understand the action of BP-1,6-Q and may help to develop novel therapies to protect against BP-1,6-Q-induced atherogenesis. Keywords BP-1,6-quinone · Glutathione · Cell death · Cytoprotection · Endothelial cells
Introduction Vascular diseases are one of the main causes of death in the United States of America (USA). About 610,000 men and women die of heart disease every year in America alone. It is estimated that one every 1 in 4 deaths in the
* Zhenquan Jia [email protected] 1
Department of Biology, The University of North Carolina At Greensboro, 312 Eberhart Building, 321 McIver Street, Greensboro, NC 27402‑6170, USA
2
Center of Excellence for Poultry Science, University of Arkansas, Fayetteville, AR 72701, USA
3
Campbell University School of Osteopathic Medicine, Buies Creek, NC, USA
USA is due to cardiovascular diseases (CVDs) [1]. Major risk factors associated with the development of cardiovascular disease include hypertension, obesi
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