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Deficiency of Circulating Monocytes Ameliorates the Progression of Myxomatous Valve Degeneration in Marfan Syndrome.
Circulation ( IF 35.5 ) Pub Date : 2020-01-13 , DOI: 10.1161/circulationaha.119.042391
Andrew J Kim 1 , Na Xu 1 , Kazuhiro Umeyama 2 , Alexia Hulin 3 , Sithara Raju Ponny 4 , Ronald J Vagnozzi 1 , Ellis A Green 1 , Paul Hanson 5 , Bruce M McManus 5 , Hiroshi Nagashima , Katherine E Yutzey 1
Affiliation  

BACKGROUND Myxomatous valve degeneration (MVD) involves the progressive thickening and degeneration of the heart valves, leading to valve prolapse, regurgitant blood flow, and impaired cardiac function. Leukocytes composed primarily of macrophages have recently been detected in myxomatous valves, but the timing of the presence and the contributions of these cells in MVD progression are not known. METHODS We examined MVD progression, macrophages, and the valve microenvironment in the context of Marfan syndrome (MFS) using mitral valves from MFS mice (Fbn1C1039G/+), gene-edited MFS pigs (FBN1Glu433AsnfsX98/+), and patients with MFS. Additional histological and transcriptomic evaluation was performed by using nonsyndromic human and canine myxomatous valves, respectively. Macrophage ontogeny was determined using MFS mice transplanted with mTomato+ bone marrow or MFS mice harboring RFP (red fluorescent protein)-tagged C-C chemokine receptor type 2 (CCR2) monocytes. Mice deficient in recruited macrophages (Fbn1C1039G/+;Ccr2RFP/RFP) were generated to determine the requirements of recruited macrophages to MVD progression. RESULTS MFS mice recapitulated histopathological features of myxomatous valve disease by 2 months of age, including mitral valve thickening, increased leaflet cellularity, and extracellular matrix abnormalities characterized by proteoglycan accumulation and collagen fragmentation. Diseased mitral valves of MFS mice concurrently exhibited a marked increase of infiltrating (MHCII+, CCR2+) and resident macrophages (CD206+, CCR2-), along with increased chemokine activity and inflammatory extracellular matrix modification. Likewise, mitral valve specimens obtained from gene-edited MFS pigs and human patients with MFS exhibited increased monocytes and macrophages (CD14+, CD64+, CD68+, CD163+) detected by immunofluorescence. In addition, comparative transcriptomic evaluation of both genetic (MFS mice) and acquired forms of MVD (humans and dogs) unveiled a shared upregulated inflammatory response in diseased valves. Remarkably, the deficiency of monocytes was protective against MVD progression, resulting in a significant reduction of MHCII macrophages, minimal leaflet thickening, and preserved mitral valve integrity. CONCLUSIONS All together, our results suggest sterile inflammation as a novel paradigm to disease progression, and we identify, for the first time, monocytes as a viable candidate for targeted therapy in MVD.

中文翻译:

循环单核细胞的缺乏改善了马凡氏综合征中粘液性瓣膜变性的进展。

背景技术粘液性瓣膜变性(MVD)涉及心脏瓣膜的进行性增厚和变性,导致瓣膜脱垂,反流的血流和心脏功能受损。最近在粘液瘤瓣膜中检测到主要由巨噬细胞组成的白细胞,但是这些细胞的存在时间和它们在MVD进展中的作用尚不清楚。方法我们使用来自MFS小鼠(Fbn1C1039G / +),基因编辑MFS猪(FBN1Glu433AsnfsX98 / +)和MFS患者的二尖瓣检查了Marfan综合征(MFS)情况下的MVD进展,巨噬细胞和瓣膜微环境。另外的组织学和转录组学评估分别通过使用非综合征的人和犬粘瘤瓣膜进行。使用移植了mTomato +骨髓的MFS小鼠或带有RFP(红色荧光蛋白)标签的CC趋化因子受体2型(CCR2)单核细胞的MFS小鼠确定巨噬细胞的个体发育。生成缺乏募集巨噬细胞(Fbn1C1039G / +; Ccr2RFP / RFP)的小鼠,以确定募集巨噬细胞对MVD进展的需求。结果MFS小鼠在2个月大时概述了粘液性瓣膜疾病的组织病理学特征,包括二尖瓣增厚,小叶细胞增多和蛋白聚糖积累和胶原蛋白断裂为特征的细胞外基质异常。MFS小鼠患病的二尖瓣同时显示浸润(MHCII +,CCR2 +)和常驻巨噬细胞(CD206 +,CCR2-)明显增加,以及增加的趋化因子活性和炎性细胞外基质修饰。同样,从基因编辑的MFS猪和患有MFS的人类患者获得的二尖瓣标本显示出通过免疫荧光检测到的单核细胞和巨噬细胞(CD14 +,CD64 +,CD68 +,CD163 +)增加。此外,对基因(MFS小鼠)和获得性MVD(人和狗)(人和狗)的比较转录组学评估揭示了患病瓣膜中共有的炎症反应上调。值得注意的是,单核细胞的缺乏可预防MVD进程,从而导致MHCII巨噬细胞显着减少,最小的小叶增厚以及保留的二尖瓣完整性。结论总之,我们的研究结果表明无菌炎症是疾病发展的新范例,并且我们首次确定了
更新日期:2020-01-14
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