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 p27Kip1 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 p27Kip1 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/p27Kip1 pathways, although it fails to reverse the cellular senescent phenotype.
Bibliographical noteFunding Information:
This work was supported by grants from the National Natural Science Foundation of China ( 81100079 , 81270183 , 81211140351 ), the Guangdong Natural Science Funds for Distinguished Young Scholar ( S2014050000048 ), the Guangdong Natural Science Foundation ( S2013010013598 ; S2011040003230 ), the New Star of Pearl River on Science and Technology of Guangzhou ( 2014J2200002 ), the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry ( 2013-693 ), the Foundation for Distinguished Young Talents in Higher Education of Guangdong ( LYM11022 ), and the Fundamental Research Funds for the Central Universities (Ji Nan University) ( 11611301 , 11612410 , 11612356 , 11614601 ), China.
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cardiology and Cardiovascular Medicine