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 p27Kip1 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 p27Kip1 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.
Bibliographical noteFunding Information:
This work was supported by grants from the National Natural Science Foundation of China ( 81100079 , 81270183 , 81211140351 ), the Guangdong Natural Science Foundation ( S2011040003230 ), the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry ( 2013-693 ), the Fundamental Research Funds for the Central Universities (Ji Nan University) ( 21611301 , 21612410 , 21612356 ), the Foundation for Distinguished Young Talents in Higher Education of Guangdong ( 34311007 ), and the Research Foundation for Recruitment Talents of Ji Nan University ( 50624058 ), China.
All Science Journal Classification (ASJC) codes
- Pathology and Forensic Medicine
- Molecular Biology
- Clinical Biochemistry