Metallothionein Protects the Heart Against Myocardial Infarction via the mTORC2/FoxO3a/Bim Pathway.

Abstract

Aims: Cardiac-specific overexpression of metallothionein (MT) has been shown to be beneficial in ischemic heart disease, but the detailed mechanisms through which MT protects against myocardial infarction (MI) remain unknown. This study assessed the involvement of the mTORC2/FoxO3a/Bim pathway in the cardioprotective effects of MT. Results: MI was induced in wild-type (FVB) mice and in cardiac-specific MT-overexpressing transgenic (MT-TG) mice by ligation of the left anterior descending (LAD) coronary artery. Cardiac function was better; infarct size and cardiomyocyte apoptosis were lower in MT-TG mice than in FVB mice after MI. Moreover, MT-TG mice exhibited better phenotypes after LAD ligation than FVB mice treated with Mn(III)tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride (MnTMPyP; a reactive oxygen species [ROS] scavenger) and cardiac-specific catalase-overexpressing transgenic (CAT-TG) mice, which showed the same ROS levels as MT-TG mice after MI. Activation of mechanistic target of rapamycin complex 2 (mTORC2) was essential for the cardioprotective effects of MT against MI. In addition, MT attenuated the downregulation of phospho-FoxO3a after MI, inhibiting the expression of the apoptosis-associated gene Bim, located downstream of FoxO3a, and reducing the level of apoptosis after MI. To mimic ischemic-injured FVB and MT-TG mice in vitro, H9c2 and MT-overexpressing H9c2 (H9c2MT7) cardiomyocytes were subjected to oxygen and glucose deprivation, with the results being consistent with those obtained in vivo. Innovation and Conclusion: The cardioprotective effects of MT against MI are not entirely dependent upon its ability to eliminate ROS. Rather, MT overexpression mostly protects against MI through the mTORC2-FoxO3a-Bim pathway.

• Authors: Mei Xue, Young A Joo, Santie Li, Chao Niu, Gen Chen, Xinchu Yi, Yangzhi Liang, Zhiwei Chen, Yingjie Shen, Weijian Ye, Lu Cai, Xu Wang, Litai Jin, Weitao Cong
• Journal: Antioxidants & redox signaling (Antioxid Redox Signal) Vol. 31 Issue 5 Pg. 403-419 (08 10 2019) ISSN: 1557-7716 [Electronic] United States
• PMID: 30860395 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bcl-2-Like Protein 11
• Bcl2l11 protein, mouse
• Cardiotonic Agents
• Forkhead Box Protein O3
• FoxO3 protein, mouse
• Reactive Oxygen Species
• Metallothionein
• Mechanistic Target of Rapamycin Complex 2

Topics

• Animals
• Apoptosis
• Bcl-2-Like Protein 11 (antagonists & inhibitors, genetics, metabolism)
• Cardiotonic Agents (metabolism)
• Cells, Cultured
• Forkhead Box Protein O3 (metabolism)
• Heart
• Mechanistic Target of Rapamycin Complex 2 (metabolism)
• Metallothionein (metabolism)
• Mice
• Mice, Inbred Strains
• Mice, Transgenic
• Myocardial Infarction (metabolism)
• Rats
• Reactive Oxygen Species (metabolism)
• Signal Transduction