Zhu Min, Goetsch Sean C, Wang Zhaoning, Luo Robert, Hill Joseph A, Schneider Jay, Morris Sidney M, Liu Zhi-Ping
From the Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX (M.Z., S.C.G., Z.W., R.L., J.A.H., J.S., Z.-P.L.); and Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, PA (S.M.M.).
Circ Res. 2015 Nov 6;117(11):967-77. doi: 10.1161/CIRCRESAHA.115.306919. Epub 2015 Oct 5.
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.
To test the hypothesis that FoxO4 promotes early post-MI inflammation via endothelial arginase 1 (Arg1).
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.
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.
心肌梗死后（MI）的炎症反应对于心肌细胞修复和伤口愈合是必要的。不幸的是，它也是随后心力衰竭病理过程的关键组成部分。转录因子叉头框O4（FoxO4）调节多种生物学过程，包括炎症反应。然而，其在心肌梗死中的作用尚不清楚。
验证FoxO4通过内皮精氨酸酶1（Arg1）促进心肌梗死后早期炎症反应的假说。
我们在野生型和FoxO4基因敲除（-/-）小鼠中诱导心肌梗死。FoxO4（-/-）小鼠心肌梗死后存活率显著更高，心脏功能更好，梗死面积减小。FoxO4（-/-）心脏中的中性粒细胞显著减少，细胞因子表达降低，竞争性一氧化氮合酶抑制剂Arg1减少。我们构建了在心肌细胞或内皮细胞中删除FoxO4的条件性FoxO4基因敲除小鼠。FoxO4内皮细胞特异性基因敲除小鼠心肌梗死后心脏功能显著改善，中性粒细胞积聚和细胞因子表达减少，而FoxO4心肌细胞特异性基因敲除小鼠的心脏功能和心肌梗死后炎症与对照同窝小鼠无显著差异。FoxO4与Arg1启动子中的Foxo结合位点结合并激活Arg1转录。在人主动脉内皮细胞中敲低FoxO4可上调缺血时的一氧化氮并抑制单核细胞黏附，这可通过Arg1的异位表达逆转。此外，野生型小鼠中Arg1的化学抑制具有与FoxO4失活类似的心脏保护作用，并减少心肌梗死后的炎症反应，而向FoxO4基因敲除小鼠施用一氧化氮合酶抑制剂可逆转FoxO4缺失对心肌梗死后心脏功能的有益作用。
FoxO4在心肌梗死反应中激活内皮细胞中的Arg1转录，导致一氧化氮下调和中性粒细胞向梗死区域浸润上调。
