title: FoxO3a suppresses the senescence of cardiac microvascular endothelial cells by regulating the ROS-mediated cell cycle.
abstract: FoxO3a plays an important role in the aging process and decreases with age. However, the potential regulatory roles of FoxO3a in processes involved in cardiac microvascular endothelial cell (CMEC) senescence, and its underlying molecular mechanisms have not been elucidated. This study demonstrates that FoxO3a is deactivated in senescent CMECs together with the inhibition of proliferation and tube formation. Furthermore, the activation of the antioxidant enzymes catalase and SOD, downstream FoxO3a targets, was significantly decreased, thereby leading to cell cycle arrest in G1-phase by increased ROS generation and subsequently the activation of the p27(Kip1) pathway. However, FoxO3a overexpression in primary low-passage CMECs not only significantly suppressed the senescence process by increasing the activation of catalase and SOD but also markedly inhibited ROS generation and p27(Kip1) activation, although it failed to reverse cellular senescence. Moreover, both cell viability and tube formation were greatly increased by FoxO3a overexpression in primary CMECs during continuous passage. In addition, FoxO3a, deficiency in low-passage CMECs, accelerated the senescence process. Collectively, our data suggest that FoxO3a suppresses the senescence process in CMECs by regulating the antioxidant/ROS/p27(Kip1) pathways, although it fails to reverse the cellular senescent phenotype.
authors: Key Laboratory for Regenerative Medicine of Ministry of Education and Department of Developmental & Regenerative Biology, Ji Nan University, Guangzhou 510632, China. Electronic address: qixufeng@jnu.edu.cn.
authors: Xu-Feng
authors: XF
authors: Qi
authors: Key Laboratory for Regenerative Medicine of Ministry of Education and Department of Developmental & Regenerative Biology, Ji Nan University, Guangzhou 510632, China.
authors: Zhuo-Ying
authors: ZY
authors: Chen
authors: Key Laboratory for Regenerative Medicine of Ministry of Education and Department of Developmental & Regenerative Biology, Ji Nan University, Guangzhou 510632, China.
authors: Jing-Bo
authors: JB
authors: Xia
authors: School of Environmental Science and Engineering, Guangdong University of Technology, Guangzhou, People's Republic of China.
authors: Li
authors: L
authors: Zheng
authors: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors: Hui
authors: H
authors: Zhao
authors: Department of Dermatology and Institute of Hair and Cosmetic Medicine, Yonsei University Wonju College of Medicine, Wonju, Gangwon 220-701, Korea.
authors: Long-Quan
authors: LQ
authors: Pi
authors: Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Gangwon 220-701, Korea.
authors: Kyu-Sang
authors: KS
authors: Park
authors: Department of Microbiology, Yonsei University Wonju College of Medicine, Wonju, Gangwon 220-701, Korea.
authors: Soo-Ki
authors: SK
authors: Kim
authors: Department of Environmental Medical Biology, Yonsei University Wonju College of Medicine, Wonju, Gangwon 220-701, Korea.
authors: Kyu-Jae
authors: KJ
authors: Lee
authors: Key Laboratory for Regenerative Medicine of Ministry of Education and Department of Developmental & Regenerative Biology, Ji Nan University, Guangzhou 510632, China. Electronic address: tdongbme@jnu.edu.cn.
authors: Dong-Qing
authors: DQ
authors: Cai
mesh_terms: D000818:Animals; D001483:Base Sequence; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival; D016922:Cellular Senescence; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics* / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D016086:Lentivirus / Q000235:genetics; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism
chemical_list: C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D017382:Reactive Oxygen Species; D050760:Cyclin-Dependent Kinase Inhibitor p27; D002374:Catalase; D008156:Luciferases; D013482:Superoxide Dismutase
keywords: Cardiac microvascular endothelial cells; Cell cycle; FoxO3a; Senescence