FoxO3α-mediated autophagy contributes to apoptosis in cardiac microvascular endothelial cells under hypoxia.

Abstract

Hypoxic injury of cardiac microvascular endothelial cells (CMECs) is an important pathophysiological event in myocardial infarction, whereas, the underlying mechanism is still poorly understood. Autophagy, a highly conserved process of cellular degradation, is required for normal cardiac function and also has been implicated in various cardiovascular diseases. Here we investigated the potential role of autophagy in CMEC dysfunction under hypoxia. CMECs were isolated from SD rats. Hypoxia (6-24h, 1% O2) induced autophagy in CMECs as evidenced by formation of punctate LC3, increased conversion of LC3-I to LC3-II and increased p62 degradation. Importantly, hypoxia-induced apoptosis in CMECs was attenuated by 3-Methyladenine (5mM), an autophagy inhibitor, and aggravated by rapamycin (1.0 μg/L), an autophagy inducer. Meanwhile, hypoxia increased the nuclear localization of FoxO3α, accompanying with the decreased phosphorylation of FoxO3α and Akt. FoxO3α silencing decreased hypoxia-induced autophagy and the resultant apoptosis. Furthermore, treatment with 3-Methyladenine (10mg/kg/day) improved the endothelial-dependent diastolic function of coronary artery in rats with myocardial infarction. These results indicated that hypoxia-induced autophagy formation in CMECs is mediated by FoxO3α and contributes to hypoxic injury of hearts.

• Authors: Ruian Wang, Qun Yang, Xia Wang, Wei Wang, Jing Li, Juanxia Zhu, Xiaohua Liu, Jian Liu, Jianqing Du
• Journal: Microvascular research (Microvasc Res) Vol. 104 Pg. 23-31 (Mar 2016) ISSN: 1095-9319 [Electronic] United States
• PMID: 26546832 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• FOXO3 protein, rat
• Forkhead Box Protein O3
• Forkhead Transcription Factors
• RNA, Small Interfering
• 3-methyladenine
• Adenine
• Sirolimus

Topics

• Adenine (analogs & derivatives, pharmacology)
• Animals
• Apoptosis (physiology)
• Autophagy (drug effects, physiology)
• Cell Hypoxia (physiology)
• Cells, Cultured
• Endothelial Cells (cytology, drug effects, metabolism)
• Forkhead Box Protein O3
• Forkhead Transcription Factors (antagonists & inhibitors, genetics, metabolism)
• Gene Silencing
• Male
• Microvessels (cytology, metabolism)
• Myocardial Infarction (drug therapy, pathology, physiopathology)
• Myocardium (cytology, metabolism)
• RNA, Small Interfering (genetics)
• Rats
• Rats, Sprague-Dawley
• Sirolimus (pharmacology)