Abstract 261: Foxo4 Promotes Early Inflammatory Response Upon Myocardial Infarction via Endothelial Arg1
Myocardial infarction (MI) can result in a maladaptive remodeling of the heart that leads to heart failure. The post-MI inflammation is necessary for wound healing. Unfortunately it is also a key component of subsequent heart failure pathology. Thus, understanding the mechanism of post-MI inflammation and identifying targets for intervention are of translational interests. To understand the role of FoxO4 in post-MI remodeling, we induced MI in WT and FoxO4 global knockout (gKO) mice by surgical ligation of the left anterior descending coronary artery. FoxO4-inactivation resulted in a significantly higher post-MI survival, better cardiac function, and reduced fibrosis and infarct size compared to WT mice. FoxO4 gKO mouse hearts had significantly less mount of neutrophils, and reduced expressions of cytokines, MMP9, and Arginase 1 (Arg1). To determine the contribution of cellular FoxO4 to the post-MI phenotype, we generated cardiomyocyte and endothelial cell specific FoxO4 knockout mice (FoxO4 cKO and eKO). While FoxO4 cKO mice showed similar post-MI phenotype to those of WT littermates, FoxO4 eKO mice had better cardiac function with reduced inflammation, neutrophil infiltration, and Arg1 expression similar to those of FoxO4 gKO mice. Since Arg1 is a competitive inhibitor of nitric oxide (NO) synthase and NO inhibits lymphocyte adhesion and transmigration across the endothelial barrier, downregulation of neutrophils in post-MI FoxO4-null mouse hearts could be due to reduced endothelial Arg1 and thus increased NO. Consistent with this hypothesis, we show that Arg1 is a direct transcriptional target of FoxO4. Endothelial FoxO4 is necessary and sufficient to activate Arg1 expression in response to hypoxia. Knockdown of FoxO4 in human aortic endothelial cells suppressed leukocyte adhesion. Furthermore, chemical inhibition of Arg1 in WT mice had similar cardioprotection following MI as FoxO4-inactivation and administration of NOS inhibitor to FoxO4 gKO mice reversed the beneficial effects of FoxO4-deletion on post-MI cardiac function. Our studies showed that FoxO4 promotes early inflammatory response via endothelial Arg1 and suggest a potential therapy to reduce the early post-MI inflammation and enhance cardiac function in MI-injured hearts.
Author Disclosures: M. Zhu: None. Z. Wang: None. R. Luo: None. S. Goetsch: None. J. Schneider: None. J. Hill: None. S. Morris Jr.: None. Z. Liu: None.
- © 2015 by American Heart Association, Inc.