Substrate stiffness-regulated matrix metalloproteinase output in myocardial cells and cardiac fibroblasts: implications for myocardial fibrosis.
Substrate stiffness-regulated matrix metalloproteinase output in myocardial cells and cardiac fibroblasts: implications for myocardial fibrosis.
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DOI：
10.1016/j.actbio.2014.01.031
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发表时间：
2014-06
影响因子：
9.7
通讯作者：
Jing Xie;Quanyou Zhang;Ting Zhu;Yanyan Zhang;Bailin Liu;Jianwen Xu;Hucheng Zhao
中科院分区：
文献类型：
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作者：
Jing Xie;Quanyou Zhang;Ting Zhu;Yanyan Zhang;Bailin Liu;Jianwen Xu;Hucheng Zhao
心肌纤维化是结构重塑的重要病理特征，可导致心室僵硬、舒张期功能障碍、心律失常，甚至可能导致猝死。基质刚性是作用于细胞的众多力学因素之一，越来越被认为是心肌细胞行为的重要介质。制备了不同硬度的聚二甲基硅氧烷(PDMS)基质以模拟生理性和病理性的心脏组织，并探讨了基质的弹性模数对心肌细胞和心脏成纤维细胞中基质降解明胶酶的调节作用。最初，随着两个细胞中PDMS硬度的增加，细胞铺展面积增加。后来的研究表明，随着PDMS底物硬度的增加，心肌细胞和心脏成纤维细胞中的MMP-2基因表达和蛋白活性都会增强，而且这种基因和蛋白相关的增加与弹性模数呈显著的线性相关。相比之下，基质金属蛋白酶-9基因和蛋白的表达只在心脏成纤维细胞中上调，而在心肌细胞中不表达。这些结果表明，心肌细胞和心肌成纤维细胞可以感觉到病理性纤维化中的僵硬，当暴露于微环境中基质僵硬增加时，基质降解明胶酶的表达显示出不同但阳性的反应。细胞感知病理性基质僵硬的现象有助于增加对心肌纤维化机制的了解，并最终可能导致制定治疗策略。
Cardiac fibrosis, an important pathological feature of structural remodeling, contributes to ventricular stiffness, diastolic dysfunction, arrhythmia and may even lead to sudden death. Matrix stiffness, one of the many mechanical factors acting on cells, is increasingly appreciated as an important mediator of myocardial cell behavior. Polydimethylsiloxane (PDMS) substrates were fabricated with different stiffnesses to mimic physiological and pathological heart tissues, and the way in which the elastic modulus of the substrate regulated matrix-degrading gelatinases in myocardial cells and cardiac fibroblasts was explored. Initially, an increase in cell spreading area was observed, concomitant with the increase in PDMS stiffness in both cells. Later, it was demonstrated that the MMP-2 gene expression and protein activity in myocardial cells and cardiac fibroblasts can be enhanced with an increase in PDMS substrate stiffness and, moreover, such gene- and protein-related increases had a significant linear correlation with the elastic modulus. In comparison, the MMP-9 gene and protein expressions were up-regulated in cardiac fibroblasts only, not in myocardial cells. These results implied that myocardial cells and cardiac fibroblasts in the myocardium could sense the stiffness in pathological fibrosis and showed a differential but positive response in the expression of matrix-degrading gelatinases when exposed to an increased stiffening of the matrix in the microenvironment. The phenomenon of cells sensing pathological matrix stiffness can help to increase understanding of the mechanism underlying myocardial fibrosis and may ultimately lead to planning cure strategies.