Fibronectin increases the force production of mouse papillary muscles via ýý5ýý1 integrin.
Fibronectin increases the force production of mouse papillary muscles via ýý5ýý1 integrin.
复制标题
纤连蛋白通过 α5α1 整合素增加小鼠乳头肌的力量产生。
DOI：
10.1016/j.yjmcc.2010.10.003
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发表时间：
2011
影响因子：
5
通讯作者：
Muthuchamy,Mariappan
中科院分区：
文献类型：
--
作者：
Wu,Xin;Chakraborty,Sanjukta;Heaps,CristineL;Davis,MichaelJ;Meininger,GeraldA;Muthuchamy,Mariappan
细胞外基质(ECM)蛋白-整合素-细胞骨架轴在许多细胞类型中作为机械转导蛋白组合发挥着核心作用。然而，机械转导的过程和由此轴产生的机械产生的信号如何影响心肌的肌丝功能还不完全清楚。我们假设ECM蛋白可以通过整合素结合来调节心脏功能，从而改变细胞内钙离子浓度([Ca~(2+)]i)和/或调节肌丝激活过程。在小鼠乳头肌的作用力测量表明，当ECM蛋白的可溶性形式--纤维连接蛋白(FN)存在时，在1赫兹、2赫兹、5赫兹和9赫兹的刺激频率下，激活力分别增加40%、54%、35%和16%。此外，在FN存在的情况下，激活力的增加与[Ca~(2+)]i增加12-33%和单位Ca~(2+)的激活力增加20-50%有关。α5整合素的功能阻断抗体可阻断FN对细胞内力和[Ca~(2+)]i的影响，而α3整合素的功能阻断抗体不能逆转FN的作用。L类钙通道阻滞剂、维拉帕米或蛋白激酶A抑制剂可逆转FN的作用。新鲜分离的心肌细胞在FN存在下，其收缩力增加39%，L钙电流增加36%。纤维经FN处理后，磷蛋白I的磷酸化水平显著增加，而肌钙蛋白I的磷酸化水平无明显变化。这些结果表明，FN通过α-5-β-1整合素作用于心肌细胞，这种作用部分是通过增加[Ca~(2+)]i和Ca~(2+)敏感性、激活PKA和磷蛋白的磷酸化来实现的。
The extracellular matrix (ECM) protein–integrin–cytoskeleton axis plays a central role as a mechanotransducing protein assemblage in many cell types. However, how the process of mechanotransduction and the mechanically generated signals arising from this axis affect myofilament function in cardiac muscle are not completely understood. We hypothesize that ECM proteins can regulate cardiac function through integrin binding, and thereby alter the intracellular calcium concentration ([Ca2+]i) and/or modulate myofilament activation processes. Force measurements made in mouse papillary muscle demonstrated that in the presence of the soluble form of the ECM protein, fibronectin (FN), active force was increased significantly by 40% at 1Hz, 54% at 2Hz, 35% at 5Hz and 16% at 9Hz stimulation frequencies. Furthermore, increased active force in the presence of FN was associated with 12–33% increase in [Ca2+]iand 20–50% increase in active force per unit Ca2+. A function blocking antibody for α5 integrin prevented the effects of the FN on the changes in force and [Ca2+]i, whereas a function blocking α3 integrin antibody did not reverse the effects of FN. The effects of FN were reversed by an L-type Ca2+channel blocker, verapamil or PKA inhibitor. Freshly isolated cardiomyocytes exhibited a 39% increase in contraction force and a 36% increase in L-type Ca2+current in the presence of FN. Fibers treated with FN showed a significant increase in the phosphorylation of phospholamban; however, the phosphorylation of troponin I was unchanged. These results demonstrate that FN acts via α5β1 integrin to increase force production in myocardium and that this effect is partly mediated by increases in [Ca2+]iand Ca2+sensitivity, PKA activation and phosphorylation of phospholamban.