Circulation Research

RES

FoxO4 Promotes Early Inflammatory Response upon Myocardial Infarction via Endothelial Arg1

FoxO4 Promotes Adverse Post-MI LV Remodeling

CIRCRES/2015/306919

10.1161/CIRCRESAHA.115.306919 117

11/06/15

Bridges-Lyman Gemma

410-3275005

410-3279322

Frangogiannis, Nikolaos Albert Einstein College of Medicine

Dr.

Zhi-Ping

Liu

zhi-ping.Liu@utsouthwestern.edu

Dr.

University of Texas Southwestern Medical Center

6000 Harry Hines Blvd

Dallas

Texas

75390

UNITED STATES

214-6481485

214-6481450

8469

Min

Zhu

University of Texas Southwestern Medical Center

Min.Zhu@utsouthwestern.edu

162603

Sean

Goetsch

University of Texas Southwestern Medical Center

Sean.Goetsch@utsouthwestern.edu

281673

Zhaoning

Wang

University of Texas Southwestern Medical Center

Zhaoning.wang@utsouthwestern.edu

299408

Robert

Luo

University of Texas Southwestern Medical Center

1998.robert@gmail.com

299252

Joseph

Hill

University of Texas Southwestern Medical Center

joseph.hill@utsouthwestern.edu

9827

Jay

Schneider

University of Texas Southwestern Medical Center

jay.schneider@utsouthwestern.edu

32738

Sidney

Morris, Jr.

University of Pittsburgh School of Medicine

smorris@pitt.edu

23840

Zhi-Ping

Liu

University of Texas Southwestern Medical Center

zhi-ping.Liu@utsouthwestern.edu

8469

05/25/2015

10/02/2015

10/05/2015

Regular Article

Arginase 1 endothelial cell FoxO4

CIRCRES/2013/302538

FoxO4 promotes adverse post myocardial infarction left ventricular remodeling by activating Arg1 expression in cardiofibroblasts

Rationale: Inflammation in post-myocardial infarct (MI) is necessary for myocyte repair and wound healing. Unfortunately it is also a key component of subsequent heart failure pathology. 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 Arg1. Methods and Results: We induced MI in WT and FoxO4-/- mice. FoxO4-/- mice mice had a significantly higher post-MI survival, better cardiac function, and reduced infarct size. FoxO4-/- micehearts had significantly fewer neutrophils, reduced expression of cytokines and competitive nitric oxide synthase (NOS) inhibitor Arginase 1 (Arg1). We generated conditional FoxO4 knockout mice with FoxO4-deleted in cardiac mycoytes (cKO) or endothelial cells (ecKO). FoxO4 ecKO mice showed significant post-MI improvement of cardiac function and reduction of neutrophil accumulation and cytokine expression whereas FoxO4 cKO 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 upon ischemia and suppressed monocyte adhesion that can be reversed by ectopic-expression of Arg1. Furthermore, chemical inhibition of Arg1 in WT mice had similar cardioprotection and reduced inflammation following MI as FoxO4-inactivation and administration of NOS 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.

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CircRes_CIRCRES-2015-306919_merge.pdf

CircRes_CIRCRES-2015-306919_Liu_8469_disclosure.pdf

CircRes_CIRCRES-2015-306919_Liu_8469_copyright.pdf

CircRes_CIRCRES-2015-306919_Zhu_162603_disclosure.pdf

CircRes_CIRCRES-2015-306919_Zhu_162603_copyright.pdf

CircRes_CIRCRES-2015-306919_Hill_9827_disclosure.pdf

CircRes_CIRCRES-2015-306919_Hill_9827_copyright.pdf

CircRes_CIRCRES-2015-306919_Goetsch_281673_disclosure.pdf

CircRes_CIRCRES-2015-306919_Goetsch_281673_copyright.pdf

CircRes_CIRCRES-2015-306919_Schneider_32738_disclosure.pdf

CircRes_CIRCRES-2015-306919_Schneider_32738_copyright.pdf

CircRes_CIRCRES-2015-306919_Luo_299252_disclosure.pdf

CircRes_CIRCRES-2015-306919_Luo_299252_copyright.pdf

CircRes_CIRCRES-2015-306919_Morris_Jr_23840_disclosure.pdf

CircRes_CIRCRES-2015-306919_Morris_Jr_23840_copyright.pdf

CircRes_CIRCRES-2015-306919_Wang_299408_disclosure.pdf

CircRes_CIRCRES-2015-306919_Wang_299408_copyright.pdf

PAP: 10/5/15 Please note that the authors have agreed to pay $425 in excess page charges. Funding: Howard Hughes Medical Institute (HHMI): No National Institutes of Health (NIH): Yes Not applicable for this manuscript: No Other: Yes Wellcome Trust: No Subject Codes: [10030] Inflammation [10033] Ischemia [10081] Gene Expression and Regulation [10099] Myocardial Infarction gbridgeslyman