Involvement of the FoxO3a pathway in the ischemia/reperfusion injury of cardiac microvascular endothelial cells.
FoxO3a, a member of the forkhead transcription factors, has been demonstrated to be involved in myocardial ischemia/reperfusion (I/R) injury. Cardiac microvascular endothelial cells (CMECs) are some of the predominant cells damaged immediately after myocardial I/R injury. Despite the importance of injured CMECs in an ischemic heart, little is known about the involvement of FoxO3a in regulating CMECs injury. Thus, we used rat CMECs following simulated I/R to examine FoxO3a activation and signaling in relation to survival, the cell cycle and apoptosis in CMECs. We found that Akt negatively regulates activation of the FoxO3a pathway by phosphorylating FoxO3a in CMECs as demonstrated with an Akt inhibitor and activator. Upon I/R injury, the FoxO3a pathway was significantly activated in CMECs, which was accompanied by Akt deactivation. In parallel, the I/R of CMECs induced G1-phase arrest through p27(Kip1) up-regulation and significant activation of caspase-3. Accordingly, inhibition of the FoxO3a pathway by IGF-1, an Akt activator, could significantly block the I/R-enhanced activation of p27(Kip1) and caspase-3 in CMECs. Collectively, our results indicate that the FoxO3a pathway is involved in the I/R injury of CMECs at least in part through the regulation of cell cycle arrest and apoptosis, suggesting that the FoxO3a pathway may be a novel therapeutic target that protects against microvascular endothelial damage in ischemic hearts.
Key Laboratory for Regenerative Medicine of Ministry of Education, Ji Nan University, Guangzhou 510632, China; Joint Laboratory for Regenerative Medicine, Chinese University of Hong Kong-Ji Nan University, Guangzhou 510632, China; International Base of Collaboration for Science and Technology (JNU), The Ministry of Science and Technology & Guangdong Province, Guangzhou 510632, China; Department of Developmental & Regenerative Biology, College of Life Science and Technology, Ji Nan University, Guangzhou 510632, China. Electronic address: qixufeng@jnu.edu.cn.
Xu-Feng
XF
Qi
Yun-Jian
YJ
Li
Zhuo-Ying
ZY
Chen
Soo-Ki
SK
Kim
Kyu-Jae
KJ
Lee
Dong-Qing
DQ
Cai
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism*; D005434:Flow Cytometry; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors
Cardiac microvascular endothelial cells; FoxO3a; Ischemia/reperfusion injury