Interleukin-37 suppresses the osteogenic responses of human aortic valve interstitial cells in vitro and alleviates valve lesions in mice
Interleukin-37 suppresses the osteogenic responses of human aortic valve interstitial cells in vitro and alleviates valve lesions in mice
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Interleukin-37在体外抑制人主动脉瓣间质细胞的成骨反应并减轻小鼠瓣膜病变
DOI：
10.1073/pnas.1619667114
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发表时间：
2017-02-14
影响因子：
11.1
通讯作者：
Meng, Xianzhong
中科院分区：
文献类型：
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作者：
Zeng, Qingchun;Song, Rui;Meng, Xianzhong
意义钙性主动脉瓣病(CAVD)是一种慢性炎症性和成骨性疾病，其潜在机制尚不清楚，也无法进行药物治疗。目前的研究表明，病变瓣膜的主动脉瓣间质细胞(AVICs)中IL-37的低水平表达在CAVD相关的瓣膜成骨活性升高中起一定作用。IL-37抑制NF-κB和ERK1/2抑制AVIC成骨反应，重组IL-37对病变瓣膜AVICs的作用更强。此外，IL-37在小鼠体内的表达可以减轻长期暴露于内毒素或高脂饮食后的主动脉瓣肥厚。因此，IL-37在人AVICs中是抗骨形成的，并且有可能限制CAVD的进展。钙化性主动脉瓣病变是一种慢性炎症过程，病变的主动脉瓣间质细胞(AVICs)在促炎刺激下表达较高水平的成骨因子。在此，我们报道了在Toll样受体(TLR)2或4刺激下，病变的人主动脉瓣动静脉内皮细胞中IL-37水平降低可能是骨形态发生蛋白-2(BMP-2)和碱性磷酸酶(ALP)表达增强的原因。重组人IL-37处理病变的AVICs可以抑制BMP-2和ALP的水平以及钙沉积的形成。在小鼠中，当长期接触TLR4激动剂或高脂饮食时，可以观察到主动脉瓣增厚；然而，表达人IL-37的小鼠表现出显著较低的BMP-2水平和较少的主动脉瓣增厚，当接受相同的方案时。高脂饮食导致小鼠主动脉瓣叶中氧化型低密度脂蛋白(OxLDL)沉积。此外，重组IL-37可抑制oxLDL诱导的人AVICs的成骨反应。从机制上讲，人血管内皮细胞对oxLDL的成骨反应减弱与IL-37抑制NF-κB和ERK1/2的能力有关。这些发现表明，人主动脉瓣病变血管内皮细胞成骨因子表达增强至少部分是由于IL-37相对缺乏。由于重组IL-37抑制了人AVICs的成骨反应，并减轻了暴露在高脂饮食或促炎刺激下的小鼠的主动脉瓣病变，因此IL-37对进行性钙化性主动脉瓣疾病具有治疗潜力。
Significance Calcific aortic valve disease (CAVD) is a chronic inflammatory and osteogenic condition with unknown underlying mechanism and unavailable pharmacological therapy. The present study shows that lower levels of IL-37 expression in aortic valve interstitial cells (AVICs) of diseased valves play a role in the elevated valvular osteogenic activity associated with CAVD. IL-37 inhibits NF-κB and ERK1/2 to suppress AVIC osteogenic responses, and recombinant IL-37 has a greater effect on AVICs of diseased valves. Moreover, expression of IL-37 in mice attenuates aortic valve thickening following a prolonged exposure to endotoxin or high fat diet. Thus, IL-37 is antiosteogenic in human AVICs and has the potential for limitation of CAVD progression. Calcific aortic valve disease is a chronic inflammatory process, and aortic valve interstitial cells (AVICs) from diseased aortic valves express greater levels of osteogenic factors in response to proinflammatory stimulation. Here, we report that lower cellular levels of IL-37 in AVICs of diseased human aortic valves likely account for augmented expression of bone morphogenetic protein-2 (BMP-2) and alkaline phosphatase (ALP) following stimulation of Toll-like receptor (TLR) 2 or 4. Treatment of diseased AVICs with recombinant human IL-37 suppresses the levels of BMP-2 and ALP as well as calcium deposit formation. In mice, aortic valve thickening is observed when exposed to a TLR4 agonist or a high fat diet for a prolonged period; however, mice expressing human IL-37 exhibit significantly lower BMP-2 levels and less aortic valve thickening when subjected to the same regimens. A high fat diet in mice results in oxidized low-density lipoprotein (oxLDL) deposition in aortic valve leaflets. Moreover, the osteogenic responses in human AVICs induced by oxLDL are suppressed by recombinant IL-37. Mechanistically, reduced osteogenic responses to oxLDL in human AVICs are associated with the ability of IL-37 to inhibit NF-κB and ERK1/2. These findings suggest that augmented expression of osteogenic factors in AVICs of diseased aortic valves from humans is at least partly due to a relative IL-37 deficiency. Because recombinant IL-37 suppresses the osteogenic responses in human AVICs and alleviates aortic valve lesions in mice exposed to high fat diet or a proinflammatory stimulus, IL-37 has therapeutic potential for progressive calcific aortic valve disease.