Key result
FoxO4 deletion in endothelial cells improved post-MI survival and cardiac function while reducing infarct size and neutrophil accumulation by downregulating Arg1.
Why the study?
Does FoxO4 deletion or inhibition reduce early inflammatory response and improve cardiac outcomes following myocardial infarction in preclinical models?
Does FoxO4 deletion or inhibition reduce early inflammatory response and improve cardiac outcomes following myocardial infarction in preclinical models?
FoxO4 promotes detrimental early post-MI inflammation via endothelial Arg1, suggesting it as a potential therapeutic target for improving post-MI healing.
Suggests endothelial FoxO4 as post-MI target; leaves open translation from animal models to humans.
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.
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Zhu et al. (2015) studied Myocardial Infarction. FoxO4 deletion vs. Wild-type / control littermates was evaluated on Post-MI survival, cardiac function, and infarct size. FoxO4 deletion in endothelial cells improved post-MI survival and cardiac function while reducing infarct size and neutrophil accumulation by downregulating Arg1.
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