FoxO4 promotes early inflammatory response upon myocardial infarction via endothelial Arg1.

Abstract

RATIONALE:

Inflammation in post-myocardial infarction (MI) is necessary for myocyte repair and wound healing. Unfortunately, it is also a key component of subsequent heart failure pathology. Transcription factor forkhead box O4 (FoxO4) regulates a variety of biological processes, including inflammation. However, its role in MI remains unknown.

OBJECTIVE:

To test the hypothesis that FoxO4 promotes early post-MI inflammation via endothelial arginase 1 (Arg1).

METHODS AND RESULTS:

We induced MI in wild-type and FoxO4(-/-) mice. FoxO4(-/-) mice had a significantly higher post-MI survival, better cardiac function, and reduced infarct size. FoxO4(-/-) hearts had significantly fewer neutrophils, reduced expression of cytokines, and competitive nitric oxide synthase inhibitor Arg1. We generated conditional FoxO4 knockout mice with FoxO4 deleted in cardiac mycoytes or endothelial cells. FoxO4 endothelial cell-specific knockout mice showed significant post-MI improvement of cardiac function and reduction of neutrophil accumulation and cytokine expression, whereas FoxO4 cardiac mycoyte-specific knockout mice had no significant difference in cardiac function and post-MI inflammation from those of control littermates. FoxO4 binds the Foxo-binding site in the Arg1 promoter and activates Arg1 transcription. FoxO4 knockdown in human aortic endothelial cells upregulated nitric oxide on ischemia and suppressed monocyte adhesion that can be reversed by ectopic-expression of Arg1. Furthermore, chemical inhibition of Arg1 in wild-type mice had similar cardioprotection and reduced inflammation after MI as FoxO4 inactivation and administration of nitric oxide synthase inhibitor to FoxO4 KO mice reversed the beneficial effects of FoxO4 deletion on post-MI cardiac function.

CONCLUSIONS:

FoxO4 activates Arg1 transcription in endothelial cells in response to MI, leading to downregulation of nitric oxide and upregulation of neutrophil infiltration to the infarct area.

• Authors: Min Zhu, Sean C Goetsch, Zhaoning Wang, Robert Luo, Joseph A Hill, Jay Schneider, Sidney M Morris Jr, Zhi-Ping Liu
• Journal: Circulation research (Circ Res) Vol. 117 Issue 11 Pg. 967-77 (Nov 06 2015) ISSN: 1524-4571 [Electronic] United States
• PMID: 26438688 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 American Heart Association, Inc.

Chemical References

• Anti-Inflammatory Agents
• Cell Cycle Proteins
• FOXO4 protein, human
• Forkhead Transcription Factors
• FoxO4 protein, mouse
• Transcription Factors
• Nitric Oxide
• ARG1 protein, human
• Arg1 protein, mouse
• Arginase

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Arginase (antagonists & inhibitors, biosynthesis, genetics)
• Binding Sites
• Cell Adhesion
• Cell Cycle Proteins
• Coculture Techniques
• Disease Models, Animal
• Endothelial Cells (drug effects, enzymology, immunology)
• Enzyme Induction
• Forkhead Transcription Factors (deficiency, genetics, metabolism)
• HEK293 Cells
• Humans
• Inflammation (enzymology, genetics, immunology, pathology, physiopathology, prevention & control)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Myocardial Infarction (enzymology, genetics, immunology, pathology, physiopathology, prevention & control)
• Myocytes, Cardiac (drug effects, enzymology, immunology, pathology)
• Neutrophil Infiltration
• Nitric Oxide (metabolism)
• Promoter Regions, Genetic
• RNA Interference
• Signal Transduction
• Time Factors
• Transcription Factors (genetics, metabolism)
• Transcription, Genetic
• Transfection
• U937 Cells