English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Plus monthly

Global: Zendy Tools annual

Global: Zendy Tools monthly

Global: Zendy Free Plan

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 andFoxO4 −/− 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 conditionalFoxO4 knockout mice withFoxO4 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, whereasFoxO4 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 asFoxO4 inactivation and administration of nitric oxide synthase inhibitor toFoxO4 KO mice reversed the beneficial effects ofFoxO4 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.

FoxO4 Promotes Early Inflammatory Response Upon Myocardial Infarction via Endothelial Arg1