title: FoxO3α-mediated autophagy contributes to apoptosis in cardiac microvascular endothelial cells under hypoxia.
abstract: Hypoxic injury of cardiac microvascular endothelial cells (CMECs) is an important pathophysiological event in myocardial infarction, whereas, the underlying mechanism is still poorly understood. Autophagy, a highly conserved process of cellular degradation, is required for normal cardiac function and also has been implicated in various cardiovascular diseases. Here we investigated the potential role of autophagy in CMEC dysfunction under hypoxia. CMECs were isolated from SD rats. Hypoxia (6-24h, 1% O2) induced autophagy in CMECs as evidenced by formation of punctate LC3, increased conversion of LC3-I to LC3-II and increased p62 degradation. Importantly, hypoxia-induced apoptosis in CMECs was attenuated by 3-Methyladenine (5mM), an autophagy inhibitor, and aggravated by rapamycin (1.0 μg/L), an autophagy inducer. Meanwhile, hypoxia increased the nuclear localization of FoxO3α, accompanying with the decreased phosphorylation of FoxO3α and Akt. FoxO3α silencing decreased hypoxia-induced autophagy and the resultant apoptosis. Furthermore, treatment with 3-Methyladenine (10mg/kg/day) improved the endothelial-dependent diastolic function of coronary artery in rats with myocardial infarction. These results indicated that hypoxia-induced autophagy formation in CMECs is mediated by FoxO3α and contributes to hypoxic injury of hearts.
authors.affiliation: Department of Physiology and Pathophysiology, Xi'an Jiaotong University, China.
authors.forename: Ruian
authors.initials: R
authors.lastname: Wang
authors.affiliation: School of Medical Psychology, Fourth Military Medical University, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Health Statistics, Fourth Military Medical University, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.affiliation: School of Medical Psychology, Fourth Military Medical University, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Physiology and Pathophysiology, Xi'an Jiaotong University, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Physiology and Pathophysiology, Xi'an Jiaotong University, China.
authors.forename: Juanxia
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Physiology and Pathophysiology, Xi'an Jiaotong University, China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Physiology and Pathophysiology, Xi'an Jiaotong University, China. Electronic address: liujian@mail.xjtu.edu.cn.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Physiology and Pathophysiology, Xi'an Jiaotong University, China.
authors.forename: Jianqing
authors.initials: J
authors.lastname: Du
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D008297:Male; D055806:Microvessels / Q000166:cytology / Q000378:metabolism; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000494:pharmacology
chemical_list: C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D034741:RNA, Small Interfering; C025946:3-methyladenine; D000225:Adenine; D020123:Sirolimus
keywords: Apoptosis; Autophagy; Cardiac microvascular endothelial cells; FoxO3α; Hypoxia