Hajj Georges P, Chu Yi, Lund Donald D, Magida Jason A, Funk Nathan D, Brooks Robert M, Baumbach Gary L, Zimmerman Kathy A, Davis Melissa K, El Accaoui Ramzi N, Hameed Tariq, Doshi Hardik, Chen BiYi, Leinwand Leslie A, Song Long-Sheng, Heistad Donald D, Weiss Robert M
From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder.
Arterioscler Thromb Vasc Biol. 2015 Jul;35(7):1653-62. doi: 10.1161/ATVBAHA.115.305729. Epub 2015 May 21.
We studied the mechanistic links between fibrocalcific changes in the aortic valve and aortic valve function in mice homozygous for a hypomorphic epidermal growth factor receptor mutation (Wave mice). We also studied myocardial responses to aortic valve dysfunction in Wave mice.
At 1.5 months of age, before development of valve fibrosis and calcification, aortic regurgitation, but not aortic stenosis, was common in Wave mice. Aortic valve fibrosis, profibrotic signaling, calcification, osteogenic markers, lipid deposition, and apoptosis increased dramatically by 6 and 12 months of age in Wave mice. Aortic regurgitation remained prevalent, however, and aortic stenosis was rare, at all ages. Proteoglycan content was abnormally increased in aortic valves of Wave mice at all ages. Treatment with pioglitazone prevented abnormal valve calcification, but did not protect valve function. There was significant left ventricular volume overload, hypertrophy, and fetal gene expression, at all ages in Wave mice with aortic regurgitation. Left ventricular systolic function was normal until 6 months of age in Wave mice, but became impaired by 12 months of age. Myocardial transverse tubules were normal in the presence of left ventricular hypertrophy at 1.5 and 3 months of age, but became disrupted by 12 months of age.
We present the first comprehensive phenotypic and molecular characterization of spontaneous aortic regurgitation and volume-overload cardiomyopathy in an experimental model. In Wave mice, fibrocalcific changes are not linked to valve dysfunction and are epiphenomena arising from structurally incompetent myxomatous valves.
我们研究了低表达表皮生长因子受体突变纯合子小鼠（Wave小鼠）主动脉瓣纤维钙化改变与主动脉瓣功能之间的机制联系。我们还研究了Wave小鼠心肌对主动脉瓣功能障碍的反应。
在1.5月龄时，即在瓣膜纤维化和钙化发展之前，Wave小鼠常见主动脉反流，但不常见主动脉狭窄。到6月龄和12月龄时，Wave小鼠的主动脉瓣纤维化、促纤维化信号传导、钙化、成骨标志物、脂质沉积和细胞凋亡显著增加。然而，主动脉反流在所有年龄段仍然普遍存在，而主动脉狭窄很少见。Wave小鼠各年龄段的主动脉瓣中蛋白聚糖含量异常增加。吡格列酮治疗可预防瓣膜异常钙化，但不能保护瓣膜功能。在有主动脉反流的Wave小鼠中，各年龄段均存在明显的左心室容量超负荷、肥厚和胎儿基因表达。Wave小鼠直到6月龄时左心室收缩功能正常，但到12月龄时受损。在1.5月龄和3月龄存在左心室肥厚时，心肌横管正常，但到12月龄时遭到破坏。
我们在一个实验模型中首次对自发性主动脉反流和容量超负荷型心肌病进行了全面的表型和分子特征描述。在Wave小鼠中，纤维钙化改变与瓣膜功能障碍无关，是由结构上功能不全的黏液瘤样瓣膜引起的附带现象。
