Deficiency of Natriuretic Peptide Receptor 2 Promotes Bicuspid Aortic Valves, Aortic Valve Disease, Left Ventricular Dysfunction, and Ascending Aortic Dilatations in Mice
Deficiency of Natriuretic Peptide Receptor 2 Promotes Bicuspid Aortic Valves, Aortic Valve Disease, Left Ventricular Dysfunction, and Ascending Aortic Dilatations in Mice
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DOI：
10.1161/circresaha.117.311194
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发表时间：
2018-02-02
影响因子：
20.1
通讯作者：
Simmons, Craig A.
中科院分区：
文献类型：
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作者：
Blaser, Mark C.;Wei, Kuiru;Simmons, Craig A.
理论基础：主动脉瓣疾病是一种细胞介导的过程，没有有效的药物治疗。CNP(C型利钠肽)抑制培养的瓣膜间质细胞的肌纤维形成和成骨，在狭窄的主动脉瓣中表达下调。然而，目前尚不清楚CNP信号是否在体内调节主动脉瓣的健康。目的：本研究的目的是确定CNP信号轴缺陷是否导致主动脉瓣疾病的加速进展。方法和结果：在培养的猪瓣间质细胞中，CNP通过鸟苷环化酶NPR2(钠尿肽受体2)抑制病理分化，而不是G蛋白偶联清除受体NPR3(钠尿肽受体3)。我们使用Npr2(+/-)和Npr2(+/-)；Ldlr(-/-)小鼠和野生型对照，在中度和晚期主动脉瓣疾病的背景下，在体内检查CNP/NPR2信号缺陷对瓣膜的影响。培养的Npr2(+/-)成纤维细胞的肌纤维形成对CNP处理不敏感，而老年Npr2(+/-)和Npr2(+/-)；Ldlr-/-小鼠出现心功能障碍和心室纤维化。与野生型相比，Npr2(+/-)和Npr2(+/-)；Ldlr(-/-)小鼠的主动脉瓣功能显著受损，瓣膜增厚、肌纤维形成、成骨、蛋白多糖合成、胶原堆积和钙化。9.4%的Npr2杂合子小鼠患有先天性二尖瓣，其主动脉瓣功能、纤维化和钙化程度较Npr2(+/-)典型三尖瓣携带者或所有野生型小鼠为差。此外，Npr2(+/-)瓣膜中CGK(cGMP依赖蛋白激酶)活性下调，CNP激活培养的猪瓣膜间质细胞合成cGMP和激活cGK1(cGMP依赖蛋白激酶1)。最后，老年Npr2(+/-)；Ldlr(-/-)小鼠出现升主动脉扩张，二尖瓣Npr2(+/-)小鼠的动脉瘤进展比三尖瓣Npr2(+/-)小鼠更大。结论：我们的数据建立了CNP/NPR2信号作为主动脉瓣发育和疾病的新调节因子，并阐明了靶向这一途径以阻止疾病进展的治疗潜力。
Rationale: Aortic valve disease is a cell-mediated process without effective pharmacotherapy. CNP (C-type natriuretic peptide) inhibits myofibrogenesis and osteogenesis of cultured valve interstitial cells and is downregulated in stenotic aortic valves. However, it is unknown whether CNP signaling regulates aortic valve health in vivo.Objective: The aim of this study is to determine whether a deficient CNP signaling axis in mice causes accelerated progression of aortic valve disease.Methods and Results: In cultured porcine valve interstitial cells, CNP inhibited pathological differentiation via the guanylate cyclase NPR2 (natriuretic peptide receptor 2) and not the G-protein-coupled clearance receptor NPR3 (natriuretic peptide receptor 3). We used Npr2(+/-) and Npr2(+/-);Ldlr(-/-) mice and wild-type littermate controls to examine the valvular effects of deficient CNP/NPR2 signaling in vivo, in the context of both moderate and advanced aortic valve disease. Myofibrogenesis in cultured Npr2(+/-) fibroblasts was insensitive to CNP treatment, whereas aged Npr2(+/-) and Npr2(+/-);Ldlr-/- mice developed cardiac dysfunction and ventricular fibrosis. Aortic valve function was significantly impaired in Npr2(+/-) and Npr2(+/-);Ldlr(-/-) mice versus wild-type littermates, with increased valve thickening, myofibrogenesis, osteogenesis, proteoglycan synthesis, collagen accumulation, and calcification. 9.4% of mice heterozygous for Npr2 had congenital bicuspid aortic valves, with worse aortic valve function, fibrosis, and calcification than those Npr2(+/-) with typical tricuspid aortic valves or all wild-type littermate controls. Moreover, cGK (cGMP-dependent protein kinase) activity was downregulated in Npr2(+/-) valves, and CNP triggered synthesis of cGMP and activation of cGK1 (cGMP-dependent protein kinase 1) in cultured porcine valve interstitial cells. Finally, aged Npr2(+/-);Ldlr(-/-) mice developed dilatation of the ascending aortic, with greater aneurysmal progression in Npr2(+/-) mice with bicuspid aortic valves than those with tricuspid valves.Conclusions: Our data establish CNP/NPR2 signaling as a novel regulator of aortic valve development and disease and elucidate the therapeutic potential of targeting this pathway to arrest disease progression.