Hypercholesterolemia induces side-specific phenotypic changes and peroxisome proliferator-activated receptor-gamma pathway activation in swine aortic valve endothelium.
Hypercholesterolemia induces side-specific phenotypic changes and peroxisome proliferator-activated receptor-gamma pathway activation in swine aortic valve endothelium.
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DOI：
10.1161/atvbaha.109.198549
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发表时间：
2010-02
期刊：
影响因子：
--
通讯作者：
Davies PF
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文献类型：
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作者：
Guerraty MA;Grant GR;Karanian JW;Chiesa OA;Pritchard WF;Davies PF
正常主动脉瓣内皮细胞在主动脉侧和室侧表现出不同的表型。在易患主动脉瓣硬化症(AVS)的主动脉侧，有促进病理和保护途径的平衡共表达。侧特异性整体基因表达可解决早期动静脉曲张的内皮表型平衡问题。成年公猪饲喂高胆固醇(HC)或等热量的正常日粮，为期2周和6个月。HC可诱导局限性脂质渗入，局限于叶的主动脉侧。对瓣膜内皮细胞群体的转录谱分析显示，易感主动脉侧对2周的高胆固醇血症比心室侧更敏感(132vs87个差异表达的基因)。然而，更高的敏感性并不是功能障碍表型的证据。相反，通路分析发现caspase3、PPAR和[Gamma]、TNF和[α]-以及NF和[kappa]B相关通路的差异表达符合保护性内皮表型；这在2周时在蛋白质水平得到证实，并持续到6个月。在高空间分辨率的大型动物模型中，主动脉瓣叶病变敏感侧的内皮细胞对高胆固醇血症有反应。提示保护性表型的转录图谱被诱导并持续存在于易发生aVS的一侧。
The endothelium of normal aortic valves expresses different phenotypes on the aortic and ventricular sides. On the aortic side, which is susceptible to aortic valve sclerosis (AVS), there is a balanced co-expression of both pro-pathological and protective pathways. Side-specific global gene expression can address endothelial phenotype balance in early AVS. Adult male swine were fed a hypercholesterolemic (HC) or an isocaloric normal diet for 2-week and 6-month periods. HC induced localized lipid insudation confined to the aortic side of the leaflet. Transcript profiling of valve endothelial populations showed that the susceptible aortic side was more sensitive to 2-weeks hypercholesterolemia than the ventricular side (1325 vs 87 genes differentially expressed). Greater sensitivity, however, was not evidence of dysfunctional phenotype. Instead, pathway analyses identified differential expression of caspase3-, PPAR&[gamma], TNF&[alpha]-, and NF&[kappa]B-related pathways that were consistent with a protective endothelial phenotype; this was confirmed at the protein level at 2 weeks and persisted at 6 months. In a large animal model at high spatial resolution, endothelium on the patho-susceptible side of the aortic valve leaflet is responsive to hypercholesterolemia. Transcript profiles indicative of a protective phenotype were induced and persisted on the side prone to AVS.