FoxO4 Promotes Early Inflammatory Response upon Myocardial Infarction via Endothelial Arg1
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.
- Received May 25, 2015.
- Revision received October 2, 2015.
- Accepted October 2, 2015.