Neurofibromin-deficient myeloid cells are critical mediators of aneurysm formation in vivo.
Neurofibromin-deficient myeloid cells are critical mediators of aneurysm formation in vivo.
复制标题
DOI：
10.1161/circulationaha.113.006320
复制
发表时间：
2014-03-18
期刊：
影响因子：
37.8
通讯作者：
Ingram DA Jr
中科院分区：
文献类型：
--
作者：
Li F;Downing BD;Smiley LC;Mund JA;Distasi MR;Bessler WK;Sarchet KN;Hinds DM;Kamendulis LM;Hingtgen CM;Case J;Clapp DW;Conway SJ;Stansfield BK;Ingram DA Jr
1型神经纤维瘤病（NF1）是一种由NF1肿瘤抑制基因突变引起的遗传性疾病。神经纤维蛋白是NF1的蛋白产物，在循环造血细胞和血管壁细胞中作为Ras活性的负调节因子，对维持血管壁稳态至关重要。NF1患者有慢性炎症导致过早心血管疾病发展的证据，包括动脉动脉瘤，这可能表现为猝死。然而，NF1动脉瘤形成的分子发病机制尚不清楚。利用血管紧张素ii诱导的动脉瘤模型，我们证明了Nf1 （Nf1+/−）的杂合失活增强了髓系细胞浸润的动脉瘤形成，并增加了血管壁的氧化应激。使用谱系限制转基因小鼠，我们发现骨髓细胞中单个Nf1等位基因的丢失足以在体内重现Nf1+/−动脉瘤表型。最后，口服辛伐他汀或抗氧化剂罗布麻素可减少Nf1+/−小鼠的动脉瘤形成。这些数据提供了遗传学和药理学证据，证明Nf1+/−髓样细胞是Nf1血管病变新模型中动脉瘤形成的细胞触发因素，并提供了潜在的治疗靶点。
Neurofibromatosis Type 1 (NF1) is a genetic disorder resulting from mutations in the NF1 tumor suppressor gene. Neurofibromin, the protein product of NF1, functions as a negative regulator of Ras activity in circulating hematopoietic and vascular wall cells, which are critical for maintaining vessel wall homeostasis. NF1 patients have evidence of chronic inflammation resulting in development of premature cardiovascular disease, including arterial aneurysms, which may manifest as sudden death. However, the molecular pathogenesis of NF1 aneurysm formation is unknown. Utilizing an angiotensin II-induced aneurysm model, we demonstrate that heterozygous inactivation of Nf1 (Nf1+/−) enhanced aneurysm formation with myeloid cell infiltration and increased oxidative stress in the vessel wall. Using lineage-restricted transgenic mice, we show loss of a single Nf1 allele in myeloid cells is sufficient to recapitulate the Nf1+/− aneurysm phenotype in vivo. Finally, oral administration of simvastatin or the antioxidant apocynin, reduced aneurysm formation in Nf1+/− mice. These data provide genetic and pharmacologic evidence that Nf1+/− myeloid cells are the cellular triggers for aneurysm formation in a novel model of NF1 vasculopathy and provide a potential therapeutic target.