Genetic Modifiers of Cardiovascular Phenotype Caused by Elastin Haploinsufficiency Act by Extrinsic Noncomplementation
Genetic Modifiers of Cardiovascular Phenotype Caused by Elastin Haploinsufficiency Act by Extrinsic Noncomplementation
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DOI：
10.1074/jbc.m111.274779
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发表时间：
2011-12-30
影响因子：
4.8
通讯作者：
Mecham, Robert P.
中科院分区：
文献类型：
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作者：
Kozel, Beth A.;Knutsen, Russell H.;Mecham, Robert P.
弹性蛋白单倍体功能不全导致与Williams-Beuren综合征和孤立性主动脉瓣上狭窄相关的心血管并发症。在这些个体的血管病理中存在显著的变异性。使用ELN(+/-)小鼠，我们试图确定这种可变性的来源。在C57BL/6J ELN(+/-)的异交后，鉴定出两个心血管参数显著偏离亲本株的背景。C57BL/6J；ELN(+/-)x129X1/SVJ的F1代血压较高，其动脉顺应性较差。相反，与DBA/2J杂交的ELN+/-动物免受与弹性蛋白缺乏相关的病理改变的影响。在交叉试验中，主动脉弹性蛋白和胶原含量与定量血管病变特征无关。对F2C57进行数量性状基因座分析；ELN(+/-)X129杂交组合在第1染色体(LOD 9.7)和第9染色体(LOD 8.7)上发现了影响血压的极显著峰值。还发现了仅影响ELN(+/-)的其他峰，包括第5号染色体上ELN上游的一个区域(LOD 4.5)。对数量性状基因座峰值的生物信息学分析揭示了几个有趣的候选基因，包括Ren1、Ncf1和NOS1；这些基因的功能与弹性纤维组装无关，但其作用可能与弹性蛋白不足协同作用，从而易患高血压和血管僵硬。实时逆转录聚合酶链式反应研究显示，在ELN(+/-)动脉中，Ncf1(NOX2 NAPDH氧化酶的一个亚单位)的背景特异性表达增加，与氧化应激增加的存在平行。这一发现提出了一种可能性，即影响活性氧产生的基因的多态通过外源性非互补改变了弹性蛋白单倍性不足患者的心血管功能。
Elastin haploinsufficiency causes the cardiovascular complications associated with Williams-Beuren syndrome and isolated supravalvular aortic stenosis. Significant variability exists in the vascular pathology in these individuals. Using the Eln(+/-) mouse, we sought to identify the source of this variability. Following outcrossing of C57Bl/6J Eln(+/-), two backgrounds were identified whose cardiovascular parameters deviated significantly from the parental strain. F1 progeny of the C57Bl/6J; Eln(+/-)x129X1/SvJ were more hypertensive and their arteries less compliant. In contrast, Eln+/- animals crossed to DBA/2J were protected from the pathologic changes associated with elastin insufficiency. Among the crosses, aortic elastin and collagen content did not correlate with quantitative vasculopathy traits. Quantitative trait locus analysis performed on F2 C57; Eln(+/-)x129 intercrosses identified highly significant peaks on chromosome 1 (LOD 9.7) for systolic blood pressure and on chromosome 9 (LOD 8.7) for aortic diameter. Additional peaks were identified that affect only Eln(+/-), including a region upstream of Eln on chromosome 5 (LOD 4.5). Bioinformatic analysis of the quantitative trait locus peaks revealed several interesting candidates, including Ren1, Ncf1, and Nos1; genes whose functions are unrelated to elastic fiber assembly, but whose effects may synergize with elastin insufficiency to predispose to hypertension and stiffer blood vessels. Real time RTPCR studies show background-specific increased expression of Ncf1 (a subunit of the NOX2 NAPDH oxidase) that parallel the presence of increased oxidative stress in Eln(+/-) aortas. This finding raises the possibility that polymorphisms in genes affecting the generation of reactive oxygen species alter cardiovascular function in individuals with elastin haploinsufficiency through extrinsic noncomplementation.