In clinical diabetic cardiomyopathy, hyperglycemia and dyslipidemia induce tissue injury, activation of cardiac fibroblasts and interstitial and perivascular fibrosis. Myofibroblasts repair the injured tissue by increasing collagen deposition in the cardiac interstitium and suppressing the activity of matrix metalloproteinases. The goal of this study was to find an ideal model to mimic the effect of high glucose concentration on human cardiac fibroblast activation. The profibrotic role of the transforming growth factor-β (TGF-β) and the protective modulation of nitric oxide were examined in two-dimensional and three-dimensional cell culture models, as well as tissue engineering models, that involved the use of cardiac fibroblasts cultured within myocardial matrix scaffolds mounted in a bioreactor that delivered biochemical and mechanical stimuli. Results showed that high glucose levels were potent pro-fibrotic stimuli. In addition, high glucose levels in concert with TGF-β constituted very strong signals that induced human cardiac fibroblast activation. Cardiac fibroblasts cultured within decellularized myocardial scaffolds and exposed to biochemical and mechanical stimuli represented an adequate model for this pathology. In conclusion, the bioreactor platform was instrumental in establishing an in vitro model of early fibrosis; this platform could be used to test the effects of various agents targeted to mitigate the fibrotic processes.

中文翻译：

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模拟糖尿病早期心脏纤维化的动态生物反应器模型

在临床糖尿病性心肌病中，高血糖和血脂异常会导致组织损伤、心脏成纤维细胞活化以及间质和血管周围纤维化。肌成纤维细胞通过增加心脏间质中的胶原沉积和抑制基质金属蛋白酶的活性来修复受损组织。本研究的目的是找到一个理想的模型来模拟高葡萄糖浓度对人心脏成纤维细胞活化的影响。转化生长因子的促纤维化作用-β（TGF-β) 和一氧化氮的保护性调节在二维和三维细胞培养模型以及组织工程模型中进行了检查，这些模型涉及使用在心肌基质支架内培养的心脏成纤维细胞，该支架安装在提供生化和机械作用的生物反应器中刺激。结果表明，高葡萄糖水平是有效的促纤维化刺激。此外，高血糖水平与 TGF-β构成了诱导人心脏成纤维细胞活化的非常强的信号。在脱细胞心肌支架内培养并暴露于生化和机械刺激的心脏成纤维细胞代表了这种病理学的适当模型。总之，生物反应器平台有助于建立一个体外早期纤维化模型；该平台可用于测试旨在减轻纤维化过程的各种药物的效果。