Folic Acid Attenuates Vascular Endothelial Cell Injury Caused by Hypoxia via the Inhibition of ERK1/2/NOX4/ROS Pathway

被引:37
作者
Cheng, Fei [1 ]
Lan, Jun [1 ]
Xia, Wenhao [2 ]
Tu, Chang [1 ]
Chen, Benfa [1 ]
Li, Shicheng [1 ]
Pan, Weibiao [1 ]
机构
[1] Dongguan Third Peoples Hosp, Dept Cardiovasc Med, 1 Xianglong Rd, Shilong Town 523326, Dongguan, Peoples R China
[2] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Hypertens & Vasc Dis, Guangzhou 510080, Guangdong, Peoples R China
关键词
Human umbilical vein endothelial cells; Hypoxia; Folic acid; Reactive oxygen species; Extracellular signal protein kinase; Endothelial nitric oxide synthase; CORONARY-ARTERY-DISEASE; CHRONIC INTERMITTENT HYPOXIA; NITRIC-OXIDE; IN-VITRO; DYSFUNCTION; SUPPLEMENTATION; FOLATE; ATHEROSCLEROSIS; HYPERTENSION; IMPROVEMENT;
D O I
10.1007/s12013-016-0723-z
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Coronary artery disease is a disease with high morbidity and mortality, in which vascular endothelial dysfunction plays an important role. Hypoxia leads to the inflammation and oxidative stress in endothelial cells, which results in the endothelial injury. The present study was designed to investigate the protective effect and mechanism of folic acid on hypoxia-induced injury in human umbilical vein endothelial cells (HUVEC). Cell counting Kit was used to detect cell survival rate, and apoptotic cells were detected by Hoechst 33258 staining. Intracellular reactive oxygen species (ROS) level was measured using dichloro-dihydro-fluorescein diacetate staining. Western blot was used to determine the protein expressions of extracellular signal protein kinase 1/2 (ERK1/2) and phosphorylated ERK1/2 (p-ERK1/2), NOX4 subunit of NAPDH and endothelial nitric oxide synthase (eNOS). Folic acid significantly increased the cell survival rate and decreased the apoptosis of HUVECs treated with folic acid compared with hypoxia-treated HUVEC. Folic acid also decreased ROS level, while it increased the nitrite content in HUVECs. In addition, folic acid decreased protein expressions of NOX4 and p-ERK1/2, while it increased the protein expression of eNOS in HUVECs. Furthermore, N-acetyl cysteine (NAC), the antioxidant, had similar effect on the cell survival rate and the apoptosis. In addition, DPI (NOX4 inhibitor) and U0126 (ERK1/2 inhibitor) rather than NAC decreased the protein expression of NOX4. NAC, DPI, and U0126 increased the protein expression of eNOS. Furthermore, U0126 rather than DPI and NAC decreased the protein expression of p-ERK1/2. Taken together, the results suggested that hypoxia decreased the cell survival rate and induced apoptosis via ERK1/2/NOX4/ROS pathway, which could be the target of folic acid in protecting the HUVECs from injury caused by hypoxia.
引用
收藏
页码:205 / 211
页数:7
相关论文
共 27 条
[21]   Folic acid reverses endothelial dysfunction induced by inhibition of tetrahydrobiopterin biosynthesis [J].
Moat, SJ ;
Clarke, ZL ;
Madhavan, AK ;
Lewis, MJ ;
Lang, D .
EUROPEAN JOURNAL OF PHARMACOLOGY, 2006, 530 (03) :250-258
[22]   NADPH oxidase-mediated reactive oxygen species production activates hypoxia-inducible factor-1 (HIF-1) via the ERK pathway after hyperthermia treatment [J].
Moon, Eui Jung ;
Sonveaux, Pierre ;
Porporato, Paolo E. ;
Danhier, Pierre ;
Gallez, Bernard ;
Batinic-Haberle, Ines ;
Nien, Yu-Chih ;
Schroeder, Thies ;
Dewhirst, Mark W. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (47) :20477-20482
[23]   Global improvement of vascular function and redox state with low-dose folic acid - Implications for folate therapy in patients with coronary artery disease [J].
Shirodaria, Cheerag ;
Antoniades, Charalambos ;
Lee, Justin ;
Jackson, Clare E. ;
Robson, Matthew D. ;
Francis, Jane M. ;
Moat, Stuart J. ;
Ratnatunga, Chandi ;
Pillai, Ravi ;
Refsum, Helga ;
Neubauer, Stefan ;
Channon, Keith M. .
CIRCULATION, 2007, 115 (17) :2262-2270
[24]   Calpain-1 Mediated Disorder of Pyrophosphate Metabolism Contributes to Vascular Calcification Induced by oxLDL [J].
Tang, Futian ;
Chan, Erqing ;
Lu, Meili ;
Zhang, Xiaowen ;
Dai, Chunmei ;
Mei, Meng ;
Zhang, Suping ;
Wang, Hongxin ;
Song, Qing .
PLOS ONE, 2015, 10 (06)
[25]   Berberine-induced decline in circulating CD31+/CD42- microparticles is associated with improvement of endothelial function in humans [J].
Wang, Jie-mei ;
Yang, Zhen ;
Xu, Ming-guo ;
Chen, Long ;
Wang, Yan ;
Su, Chen ;
Tao, Jun .
EUROPEAN JOURNAL OF PHARMACOLOGY, 2009, 614 (1-3) :77-83
[26]   Selenium attenuates ROS-mediated apoptotic cell death of injured spinal cord through prevention of mitochondria dysfunction;: in vitro and in vivo study [J].
Yeo, Jee Eun ;
Kim, Jeong Hwan ;
Kang, Soo Kyung .
CELLULAR PHYSIOLOGY AND BIOCHEMISTRY, 2008, 21 (1-3) :225-238
[27]   Atherosclerosis and folic acid supplementation trial in chronic renal failure: Baseline results [J].
Zoungas, S ;
Branley, P ;
Kerr, PG ;
Ristevski, S ;
Muske, C ;
Demos, L ;
Atkins, RC ;
Becker, G ;
Fraenkel, M ;
Hutchison, BG ;
Walker, R ;
McNeil, JJ ;
McGrath, BP .
NEPHROLOGY, 2004, 9 (03) :130-141