Age-related changes in aortic valve hemostatic protein regulation.
Age-related changes in aortic valve hemostatic protein regulation.
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DOI：
10.1161/atvbaha.113.301936
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发表时间：
2014-01
期刊：
影响因子：
--
通讯作者：
Grande-Allen KJ
中科院分区：
文献类型：
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作者：
Balaoing LR;Post AD;Liu H;Minn KT;Grande-Allen KJ
与血管内皮细胞相比，瓣膜内皮细胞（VECs）具有独特的反应，但瓣膜对止血的调节机制尚未完全明确。人的心脏瓣膜在一生中会不断重塑，导致细胞外基质（ECM）成分和组织力学性能发生变化，这可能会影响VEC的止血功能。本研究评估了VEC在原位和体外对止血的调节作用与样本年龄的关系。
将猪主动脉瓣（PAV）分为三个年龄组：幼年组（6周）、成年组（6个月）和老年组（2年）。瓣膜的组织学研究显示，分泌的促血栓形成/抗血栓形成蛋白定位于瓣膜内皮和组织内部。幼年组猪主动脉瓣内皮细胞（PAVECs）中血管性血友病因子（VWF）、组织因子途径抑制剂和组织纤溶酶原激活剂的基因表达及免疫染色高于老年组，而老年组纤溶酶原激活剂抑制剂 - 1的水平高于幼年组和成年组。组胺刺激幼年组PAVECs释放的VWF蛋白浓度高于老年组，但裂解的VWF - 140片段在各年龄组之间无差异。使用瓣膜间质细胞（VICs）建立的主动脉瓣钙化性疾病（CAVD）体外模型证实，培养物中的VWF显著增加了VIC结节形成和钙化。
主动脉瓣组织和VECs中止血蛋白的调节随年龄而变化。VWF和其他潜在止血蛋白的存在会增加体外VIC的钙化。因此，老年瓣膜储存止血蛋白的能力增强，以及与年龄相关的ECM结构丧失，使得有必要研究这些蛋白在钙化结节形成中的潜在作用。
While valvular endothelial cells (VECs) have unique responses compared to vascular ECs, valvular regulation of hemostasis is not well understood. Heart valves remodel throughout a person's lifetime, resulting in changes in extracellular matrix (ECM) composition and tissue mechanical properties that may affect VEC hemostatic function. This work assessed VEC regulation of hemostasis in situ and in vitro as a function of specimen age. Porcine aortic valves (PAV) were assigned into one of three age groups: YNG (6 weeks), ADT (6 months), or OLD (2 years). Histology of valves showed that secreted thrombotic/anti-thrombotic proteins localize at the valve endothelium, and tissue interior. Gene expression and immunostains for von Willebrand factor (VWF), tissue factor pathway inhibitor, and tissue plasminogen activator in YNG PAVECs was higher than in OLD, while plasminogen activator inhibitor-1 levels in OLD were higher than in YNG and ADT. Histamine stimulated YNG PAVECs released higher concentrations of VWF proteins than OLD, while the fraction of cleaved VWF-140 fragments were not different between age groups. A CAVD in vitro model using valvular interstitial cells (VICs) confirmed that VWF in culture significantly increased VIC nodule formation and calcification. Hemostatic protein regulation in AV tissues and VECs changes with age. The presence of VWF and other potential hemostatic proteins increase VIC calcification in vitro. Therefore, the increased capacity of elderly valves to sequester the hemostatic proteins, together with age-associated loss of ECM organization warrants investigation into potential roles for these proteins in the formation of calcific nodules.