Cyclical mechanical stretch modulates expression of collagen I and collagen III by PKC and tyrosine kinase in cardiac fibroblasts
Cyclical mechanical stretch modulates expression of collagen I and collagen III by PKC and tyrosine kinase in cardiac fibroblasts
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DOI：
10.1152/ajpregu.00804.2006
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发表时间：
2007-11-01
影响因子：
2.8
通讯作者：
Gekle, Michael
中科院分区：
文献类型：
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作者：
Husse, Britta;Briest, Wilfried;Gekle, Michael
机械负荷和化学因素作为刺激细胞外基质（ECM）的不同模式可能是心功能障碍的原因。由于成纤维细胞既能合成也能降解ECM，因此在24 h内对成年大鼠心室成纤维细胞进行三种不同伸长（3%、6%、9%）和四种不同血清浓度（0%、0.5%、5%、10%）的周期性机械拉伸（CMS; 0.33 Hz）。通过RNase保护实验分析胶原I和III以及基质金属蛋白酶-2 （MMP- 2）、MMP- 2组织抑制剂（TIMP-2）和胶原蛋白的表达。在无血清的情况下，9% CMS使ⅰ型胶原mRNA增加1.70倍，ⅲ型胶原mRNA增加1.64倍。抑制PKC或酪氨酸激酶可阻止这种增加，但不抑制PKA。抑制PKC或酪氨酸激酶本身可降低胶原I和胶原III mRNA的表达。MMP- 2、TIMP-2、colligin mRNA均表现出相同的拉伸趋势。6% CMS与10%血清联合使用，可降低I型胶原mRNA（0.62倍）和III型胶原mRNA（0.79倍）。抑制PKC或酪氨酸激酶，而不抑制PKA，可阻止10%血清中胶原I和胶原III mRNA的减少。结果表明，成纤维细胞对CMS的反应与血清浓度有关。至少有两条信号通路参与拉伸诱导的ECM调控。ECM重塑引起的心肌纤维化可导致心力衰竭的功能障碍，这可能归因于血流动力学负荷的变化。
Mechanical load and chemical factors as stimuli for the different pattern of the extracellular matrix (ECM) could be responsible for cardiac dysfunction. Since fibroblasts can both synthesize and degrade ECM, ventricular fibroblasts from adult rat hearts underwent cyclical mechanical stretch (CMS; 0.33 Hz) by three different elongations ( 3%,6%, 9%) and four different serum concentrations (0%, 0.5%, 5%, 10%) within 24 h. Expression of collagen I and III, as well as matrix metalloproteinase-2 (MMP- 2), tissue inhibitor of MMP- 2 (TIMP-2), and colligin were analyzed by RNase protection assay. In the absence of serum, 9% CMS increased the mRNA of collagen I by 1.70- fold and collagen III by 1.64-fold. This increase was prevented by the inhibition either of PKC or of tyrosine kinase but not of PKA. Inhibition of PKC or tyrosine kinase itself reduced the expression of collagen I and collagen III mRNA. The mRNA of MMP- 2, TIMP-2, and colligin showed the same tendency by stretch. Combined with 10% serum, 6% CMS reduced the mRNA of collagen I (0.62-fold) and collagen III ( 0.79fold). Inhibition of PKC or tyrosine kinase, but not of PKA, prevented the reduction of collagen I and collagen III mRNA in 10% serum. The results show that the response of fibroblasts to CMS depends on the serum concentration. At least two signaling pathways are involved in the stretch-induced ECM regulation. Myocardial fibrosis due to ECM remodeling contributes to the dysfunction of the failing heart, which might be attributed to changes in hemodynamic loading.