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Abstract：
Inflammation and endothelial dysfunction play an essential role in heart failure (HF). Epidermal growth factor-like protein 7 (EGFL7) is upregulated during pathological hypoxia and exerts a protective role. However, it is unclear whether there is a link between abnormal EGFL7 expression and inflammation in overload stress-induced heart failure. Our results showed that EGFL7 transiently increased during the early 4 weeks of TAC and in hypertensive patients without heart failure. However, it decreased to the basal line in the heart tissue 8 weeks post-transverse aortic constriction (TAC) or hypertensive patients with heart failure. Knockdown of EGFL7 with siRNA in vivo accelerated cardiac dysfunction, fibrosis, and macrophage infiltration 4 weeks after TAC. Deletion of macrophages in siRNA-EGFL7-TAC mice rescued that pathological phenotype. In vitro research revealed the mechanism. PI3K γ /AKT/N FκB signaling in macrophages was activated by the supernatant from endothelial cells stimulated by siRNA-EGFL7+phenylephrine. More macrophages adhered to endothelial cells, but pretreatment of macrophages with PI3Kγ inhibitors decreased the adhesion of macrophages to endothelial cells. Ultimately, treatment with recombinant rmEGFL7 rescued cardiac dysfunction and macrophage infiltration in siRNA-EGFL7-TAC mice. In conclusion, EGFL7 is a potential inhibitor of macrophage adhesion to mouse aortic endothelial cells. The downregulation of EGFL7 combined with increased macrophage infiltration further promoted cardiac dysfunction under pressure overload stress. Mechanistically, EGFL7 reduced endothelial cell adhesion molecule expression and inhibited the PI3K γ /AKT/NF κ B signaling pathway in macrophages.
摘要：
炎症和内皮功能障碍在心力衰竭（HF）中起着至关重要的作用。表皮生长因子样蛋白7（EGFL7）在病理性缺氧期间上调，并发挥保护作用。然而,目前尚不清楚在超负荷应激诱导的心力衰竭中EGFL7表达异常与炎症之间是否存在关联.我们的结果表明，在TAC的早期4周和无心力衰竭的高血压患者中，EGFL7短暂增加。然而,在横主动脉缩窄（TAC）或合并心力衰竭的高血压患者8周后，它在心脏组织中降至基线。用siRNA敲除EGFL7在体内加速心脏功能障碍,纤维化，TAC后4周巨噬细胞浸润。siRNA-EGFL7-TAC小鼠中巨噬细胞的缺失挽救了该病理表型。体外研究揭示了该机制。巨噬细胞中的PI3Kγ/AKT/NFκB信号通过siRNA-EGFL7+去氧肾上腺素刺激的内皮细胞上清液激活。更多的巨噬细胞粘附在内皮细胞上，但是用PI3Kγ抑制剂预处理巨噬细胞会降低巨噬细胞对内皮细胞的粘附。最终,重组rmEGFL7治疗可挽救siRNA-EGFL7-TAC小鼠的心功能障碍和巨噬细胞浸润。总之,EGFL7是巨噬细胞粘附到小鼠主动脉内皮细胞的潜在抑制剂。EGFL7的下调与巨噬细胞浸润的增加进一步促进了压力超负荷应激下的心功能障碍。机械上,EGFL7降低巨噬细胞内皮细胞粘附分子的表达，抑制PI3Kγ/AKT/NFκB信号通路。
