Chu Yi, Lund Donald D, Doshi Hardik, Keen Henry L, Knudtson Kevin L, Funk Nathan D, Shao Jian Q, Cheng Justine, Hajj Georges P, Zimmerman Kathy A, Davis Melissa K, Brooks Robert M, Chapleau Mark W, Sigmund Curt D, Weiss Robert M, Heistad Donald D
From the Departments of Internal Medicine (Y.C., D.D.L., H.D., N.D.F., J.C., G.P.H., K.A.Z., M.K.D., R.M.B., M.W.C., R.M.W., D.D.H.), Pharmacology (H.L.K., C.D.S., D.D.H.), Molecular Physiology and Biophysics (M.W.C.), Central Microscopy Research Facility (J.Q.S.), Iowa Institute of Human Genetics Genomics Division (K.L.K.), University of Iowa Carver College of Medicine, Iowa City; Veterans Administration Medical Center, Iowa City (M.W.C.); and Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder (D.D.H.).
Arterioscler Thromb Vasc Biol. 2016 Mar;36(3):466-74. doi: 10.1161/ATVBAHA.115.306912. Epub 2016 Jan 14.
Hypercholesterolemia and hypertension are associated with aortic valve stenosis (AVS) in humans. We have examined aortic valve function, structure, and gene expression in hypercholesterolemic/hypertensive mice.
Control, hypertensive, hypercholesterolemic (Apoe(-/-)), and hypercholesterolemic/hypertensive mice were studied. Severe aortic stenosis (echocardiography) occurred only in hypercholesterolemic/hypertensive mice. There was minimal calcification of the aortic valve. Several structural changes were identified at the base of the valve. The intercusp raphe (or seam between leaflets) was longer in hypercholesterolemic/hypertensive mice than in other mice, and collagen fibers at the base of the leaflets were reoriented to form a mesh. In hypercholesterolemic/hypertensive mice, the cusps were asymmetrical, which may contribute to changes that produce AVS. RNA sequencing was used to identify molecular targets during the developmental phase of stenosis. Genes related to the structure of the valve were identified, which differentially expressed before fibrotic AVS developed. Both RNA and protein of a profibrotic molecule, plasminogen activator inhibitor 1, were increased greatly in hypercholesterolemic/hypertensive mice.
Hypercholesterolemic/hypertensive mice are the first model of fibrotic AVS. Hypercholesterolemic/hypertensive mice develop severe AVS in the absence of significant calcification, a feature that resembles AVS in children and some adults. Structural changes at the base of the valve leaflets include lengthening of the raphe, remodeling of collagen, and asymmetry of the leaflets. Genes were identified that may contribute to the development of fibrotic AVS.
高胆固醇血症和高血压与人类主动脉瓣狭窄（AVS）相关。我们研究了高胆固醇血症/高血压小鼠的主动脉瓣功能、结构和基因表达。
对对照小鼠、高血压小鼠、高胆固醇血症（Apoe(-/-)）小鼠和高胆固醇血症/高血压小鼠进行了研究。严重主动脉狭窄（超声心动图检查）仅发生在高胆固醇血症/高血压小鼠中。主动脉瓣钙化极少。在瓣膜基部发现了一些结构变化。高胆固醇血症/高血压小鼠的瓣叶间嵴（或小叶间的缝）比其他小鼠更长，小叶基部的胶原纤维重新定向形成网状。在高胆固醇血症/高血压小鼠中，瓣叶不对称，这可能导致产生AVS的变化。在狭窄的发育阶段，使用RNA测序来识别分子靶点。鉴定出了与瓣膜结构相关的基因，这些基因在纤维化AVS发生之前差异表达。促纤维化分子纤溶酶原激活物抑制剂1的RNA和蛋白质在高胆固醇血症/高血压小鼠中均大幅增加。
高胆固醇血症/高血压小鼠是纤维化AVS的首个模型。高胆固醇血症/高血压小鼠在无明显钙化的情况下发生严重AVS，这一特征类似于儿童和一些成人的AVS。瓣膜小叶基部的结构变化包括嵴的延长、胶原重塑和小叶不对称。鉴定出了可能有助于纤维化AVS发展的基因。
