VEGF-A promotes angiogenesis after acute myocardial infarction through increasing ROS production and enhancing ER stress-mediated autophagy

被引:179
作者
Zou, Jiang [1 ,2 ]
Fei, Qin [1 ,2 ]
Xiao, Hui [1 ,2 ]
Wang, Hao [1 ,2 ]
Liu, Ke [1 ,2 ]
Liu, Meidong [1 ,2 ]
Zhang, Huali [1 ,2 ]
Xiao, Xianzhong [1 ,2 ]
Wang, Kangkai [1 ,2 ,3 ]
Wang, Nian [1 ,2 ]
机构
[1] Cent S Univ, Sch Basic Med Sci, Dept Pathophysiol, Changsha, Hunan, Peoples R China
[2] Cent S Univ, Key Lab Sepsis Translat Med Hunan, Changsha, Hunan, Peoples R China
[3] Cent S Univ, Xiangya Sch Med, Dept Lab Anim, Hunan Key Lab Anim Models Human Dis, Changsha, Hunan, Peoples R China
基金
中国国家自然科学基金;
关键词
angiogenesis; autophagy; ER stress; ROS; VEGF-A; ENDOPLASMIC-RETICULUM STRESS; ENDOTHELIAL GROWTH-FACTOR; CELL-DEATH; OXIDATIVE STRESS; EXPRESSION; APOPTOSIS; INJURY; CONTRIBUTES; MECHANISMS; ISCHEMIA;
D O I
10.1002/jcp.28395
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Proangiogenesis is generally regarded as an effective approach for treating ischemic heart disease. Vascular endothelial growth factor (VEGF)-A is a strong and essential proangiogenic factor. Reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, and autophagy are implicated in the process of angiogenesis. This study is designed to clarify the regulatory mechanisms underlying VEGF-A, ROS, ER stress, autophagy, and angiogenesis in acute myocardial infarction (AMI). A mouse model of AMI was successfully established by occluding the left anterior descending coronary artery. Compared with the sham-operated mice, the microvessel density, VEGF-A content, ROS production, expression of vascular endothelial cadherin, positive expression of 78kDa glucose-regulated protein/binding immunoglobulin protein (GRP78/Bip), and LC3 puncta in CD31-positive endothelial cells of the ischemic myocardium were overtly elevated. Moreover, VEGF-A exposure predominantly increased the expression of beclin-1, autophagy-related gene (ATG) 4, ATG5, inositol-requiring enzyme-1 (IRE-1), GRP78/Bip, and LC3-II/LC3-I as well as ROS production in the human umbilical vein endothelial cells (HUVECs) in a dose and time-dependent manner. Both beclin-1 small interfering RNA and 3-methyladenine treatment predominantly mitigated VEGF-A-induced tube formation and migration of HUVECs, but they failed to elicit any notable effect on VEGF-A-increased expression of GRP78/Bip. Tauroursodeoxycholic acid not only obviously abolished VEGF-A-induced increase of IRE-1, GRP78/Bip, beclin-1 expression, and LC3-II/LC3-I, but also negated VEGF-A-induced tube formation and migration of HUVECs. Furthermore, N-acetyl- l-cysteine markedly abrogated VEGF-A-increased ROS production, IRE-1, GRP78/Bip, beclin-1 expression, and LC3-II/LC3-I in the HUVECs. Taken together, our data demonstrated that increased spontaneous production of VEGF-A may induce angiogenesis after AMI through initiating ROS-ER stress-autophagy axis in the vascular endothelial cells.
引用
收藏
页码:17690 / 17703
页数:14
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