Abstract 13276: FoxO4 Promotes Post Myocardial Infarction Left Ventricular Remodeling
Myocardial infarction (MI) can result in a maladaptive remodeling of left ventricles (LV) that leads to LV dysfunction and eventual heart failure. Forkhead box O transcription factors (FoxO1, O3, and O4) are involved in many biological and disease processes such as apoptosis, and cell differentiation. They also have different roles in vascular and cardiac biology. FoxO1 and O3 have been shown to promote post-MI cardiomyocyte survival through induction of antioxidants and cell survival pathways. However, the role of FoxO4 in post-MI LV remodeling remains elusive.
To establish the mechanisms underlying FoxO4-regulated post-MI remodeling, we induced MI in WT and Foxo4-/- mice by ligation of the left anterior descending coronary artery. Unlike FoxO1 and O3, inactivation of Foxo4 in mice resulted in a significantly higher post-MI survival rate, reduced infarct size and fibrosis, and improved cardiac function. Gene profiling analysis showed significantly reduced MMP9 in Foxo4-/- mice compared to that of WT mice. More importantly, we identified Arginase 1 (Arg1) as a novel transcriptional target of FoxO4. Arg1 was transiently upregulated early in cardiac fibroblasts of infarct area. This upregulation was significantly attenuated in Foxo4-/- mice. In vitro study found that FoxO4 binds Arg1 promoter and activates its transcription. Our study also found that application of Arginase inhibitor, S-(2-boronoethyl)-L-cysteine, improved cardiac function post-MI in wild type mice. Since Arg1 degrades the sole substrate of nitric oxide (NO) synthase, L-arginine, upregulation of Arg1 may reduce arginine bioavailability for production of NO. Arg1 was also known to promote collagen production via increased proline synthesis. We found that both TGF-β-induced Arg1 expression and collagen expression were impaired in Foxo4 knocked-down cardiofibroblasts in vitro.
In conclusion, our study showed that FoxO4 plays a unique role in promoting pathological post-MI ventricular remodeling and suggests a novel cellular and molecular mechanism by which FoxO4 activates Arg1 transcription in cardiofibroblasts. FoxO4 may be a new therapeutic target that can influence ventricular remodeling post-MI.
- © 2013 by American Heart Association, Inc.