Increased afterload induces pathological cardiac hypertrophy: a new in vitro model.
Increased afterload induces pathological cardiac hypertrophy: a new in vitro model.
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DOI：
10.1007/s00395-012-0307-z
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发表时间：
2012-11
影响因子：
9.5
通讯作者：
Eschenhagen T
中科院分区：
文献类型：
--
作者：
Hirt MN;Sörensen NA;Bartholdt LM;Boeddinghaus J;Schaaf S;Eder A;Vollert I;Stöhr A;Schulze T;Witten A;Stoll M;Hansen A;Eschenhagen T
后负荷增加导致“病理性”心脏肥大，这是心力衰竭发展的最重要危险因素。目前的体外模型在解释后负荷增强诱导的心肌肥大机制方面存在不足。本研究的目的是开发一种实验模型，允许调查后负荷增强（AE）的影响，在体外工作的心肌。将基于纤维蛋白的工程化心脏组织（EHT）以24孔细胞培养形式浇铸在两个中空弹性硅胶桩之间。2周后，用金属支架加固柱子，这显著增加了自发跳动的EHTs的后负荷。建立了无血清、三碘甲状腺原氨酸和氢化可的松补充的培养基条件，以防止不确定的血清效应。对照EHT在没有加固的情况下进行相同处理。内皮素-1（ET-1）或苯丙氨酸（PE）刺激的EHT作为肥大的阳性对照。通过肌营养不良蛋白染色确定，AE下EHT中的心肌细胞扩大了28.4%，ET-1或PE刺激（40.6%或23.6%）的程度相似。心肌细胞肥大伴随着胎儿基因程序的激活，葡萄糖消耗增加，mRNA水平和胶原蛋白-1的细胞外沉积增加。重要的是，后负荷增强的EHT在释放金属支架后立即表现出收缩力降低和舒张松弛受损。这些有害的影响后负荷增强是可以预防的内皮素-A，但不能内皮素-B受体阻滞剂。EHT单独的持续后负荷增强足以诱导病理性心脏重塑，收缩功能降低，葡萄糖消耗增加。该模型将有助于以简单快速的方式研究新的治疗方法。本文的在线版本（doi：10.1007/s 00395 -012-0307-z）包含补充材料，可供授权用户使用。
Increased afterload results in ‘pathological’ cardiac hypertrophy, the most important risk factor for the development of heart failure. Current in vitro models fall short in deciphering the mechanisms of hypertrophy induced by afterload enhancement. The aim of this study was to develop an experimental model that allows investigating the impact of afterload enhancement (AE) on work-performing heart muscles in vitro. Fibrin-based engineered heart tissue (EHT) was cast between two hollow elastic silicone posts in a 24-well cell culture format. After 2 weeks, the posts were reinforced with metal braces, which markedly increased afterload of the spontaneously beating EHTs. Serum-free, triiodothyronine-, and hydrocortisone-supplemented medium conditions were established to prevent undefined serum effects. Control EHTs were handled identically without reinforcement. Endothelin-1 (ET-1)- or phenylephrine (PE)-stimulated EHTs served as positive control for hypertrophy. Cardiomyocytes in EHTs enlarged by 28.4 % under AE and to a similar extent by ET-1- or PE-stimulation (40.6 or 23.6 %), as determined by dystrophin staining. Cardiomyocyte hypertrophy was accompanied by activation of the fetal gene program, increased glucose consumption, and increased mRNA levels and extracellular deposition of collagen-1. Importantly, afterload-enhanced EHTs exhibited reduced contractile force and impaired diastolic relaxation directly after release of the metal braces. These deleterious effects of afterload enhancement were preventable by endothelin-A, but not endothelin-B receptor blockade. Sustained afterload enhancement of EHTs alone is sufficient to induce pathological cardiac remodeling with reduced contractile function and increased glucose consumption. The model will be useful to investigate novel therapeutic approaches in a simple and fast manner. The online version of this article (doi:10.1007/s00395-012-0307-z) contains supplementary material, which is available to authorized users.
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