title: FoxO3a modulates hypoxia stress induced oxidative stress and apoptosis in cardiac microvascular endothelial cells.
abstract: Cardiac microvascular endothelial cells (CMECs) dysfunction induced by hypoxia is an important pathophysiological event in myocardium ischemic injury, whereas, the underlying mechanism is not fully clarified. FoxO transcription factors regulate target genes involved in apoptosis and cellular reactive oxygen species (ROS) production. Therefore, the present study was designed to elucidate the potential role of FoxOs on the hypoxia-induced ROS formation and apoptosis in CMECs. Exposure to low oxygen tension stimulated ROS accumulation and increased apoptosis in CMECs within 6-24 h. Hypoxia also significantly increased the expressions of HIF-1α and FoxO3a. However, hypoxia decreased the phosphorylation of Akt and FoxO3a, correlated with increased nuclear accumulation. Conversely, the expression of FoxO1 was not significantly altered by hypoxia. After inhibition of HIF-1α by siRNA, we observed that hypoxia-induced ROS accumulation and apoptosis of CMECs were decreased. Meanwhile, knockdown of HIF-1α also inhibited hypoxia induced FoxO3a expression in CMECs, but did not affect FoxO1 expression. Furthermore, hypoxia-induced ROS formation and apoptosis in CMECs were correlated with the disturbance of Bcl-2 family proteins, which were abolished by FoxO3a silencing with siRNA. In conclusion, our data provide evidence that FoxO3a leads to ROS accumulation in CMECs, and in parallel, induces the disturbance of Bcl-2 family proteins which results in apoptosis.
authors.affiliation: Department of Cardiology, The Seventh People's Hospital of Zhengzhou, Zhengzhou, China.
authors.forename: Shenwei
authors.initials: S
authors.lastname: Zhang
authors.forename: Yilin
authors.initials: Y
authors.lastname: Zhao
authors.forename: Ming
authors.initials: M
authors.lastname: Xu
authors.forename: Li
authors.initials: L
authors.lastname: Yu
authors.forename: Yujie
authors.initials: Y
authors.lastname: Zhao
authors.forename: Jianghong
authors.initials: J
authors.lastname: Chen
authors.forename: Yiqiang
authors.initials: Y
authors.lastname: Yuan
authors.forename: Qiangsun
authors.initials: Q
authors.lastname: Zheng
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Niu
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D015687:Cell Hypoxia; D003331:Coronary Vessels / Q000166:cytology / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism / Q000502:physiology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008297:Male; D018384:Oxidative Stress; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species