Simm A, Nestler M, Hoppe V
Theodor-Boveri-Institut für Biowissenschaften (Biozentrum) der Universität, Physiologische Chemie II, Würzburg, Germany.
J Mol Cell Cardiol. 1997 Jan;29(1):357-68. doi: 10.1006/jmcc.1996.0280.
The heart responds to increased haemodynamic load with growth of the ventricles. The rise in ventricle mass is due to increasing mass of the myocytes and proliferation of fibroblasts and smooth muscle cells. The accompanying adaptation and remodelling of the interstitium, e.g. production and composition of the extracellular matrix proteins, determine a physiological or pathophysiological hypertrophy. Fibroblasts play a critical role in this process as the producers of extracellular matrix proteins. So far the growth factors involved are not well defined, and therefore we investigated the effect of platelet-derived growth factor (PDGF) isoforms on cellular proliferation of fibroblasts from adult rat hearts. Unlike other cell types of the cardiovascular system (e.g. smooth muscle cells), PDGF-AA has an extraordinarily high stimulatory effect on cell growth of these fibroblasts. It induces cell division to nearly the same extent and with the same kinetics as PDGF-BB as shown by cell number and flow cytometry. Cardiac fibroblasts do not express an unusually high number of PDGF alpha-receptors, (15300 PDGF alpha-receptors. 24800 PDGF beta-receptors per cell) which could explain this effect. The alpha-receptors display a lower and shorter autophosphorylation after stimulation with PDGF in comparison to the beta-receptors. The activation of the MAP kinase pathway is not different after stimulation with both PDGF isoforms. Interestingly, quiescent cardiac fibroblasts contain a preactivated p70S6-kinase. The specific drug rapamycin not only inhibits the p70S6-kinase activation but also PDGF induced cell proliferation for more than 50%. Because the p70S6-kinase activation is implicated in growth regulation in this cell system, the preactivation of this kinase is discussed to be a possible explanation for the enhanced growth effect of PDGF-AA.
心脏通过心室生长来应对增加的血流动力学负荷。心室质量的增加是由于心肌细胞质量增加以及成纤维细胞和平滑肌细胞增殖。间质随之发生的适应性改变和重塑，例如细胞外基质蛋白的产生和组成，决定了生理性或病理性肥大。成纤维细胞作为细胞外基质蛋白的产生者，在这一过程中起关键作用。到目前为止，所涉及的生长因子尚未明确界定，因此我们研究了血小板衍生生长因子（PDGF）异构体对成年大鼠心脏成纤维细胞增殖的影响。与心血管系统的其他细胞类型（如平滑肌细胞）不同，PDGF-AA对这些成纤维细胞的细胞生长具有极高的刺激作用。细胞数量和流式细胞术显示，它诱导细胞分裂的程度和动力学与PDGF-BB几乎相同。心脏成纤维细胞并未表达异常高数量的PDGFα受体（每个细胞有15300个PDGFα受体、24800个PDGFβ受体），这无法解释这种效应。与β受体相比，α受体在用PDGF刺激后显示出较低且较短的自身磷酸化。两种PDGF异构体刺激后，MAP激酶途径的激活并无差异。有趣的是，静止的心脏成纤维细胞含有预激活的p70S6激酶。特异性药物雷帕霉素不仅抑制p70S6激酶的激活，还使PDGF诱导的细胞增殖减少50%以上。由于该细胞系统中p70S6激酶的激活与生长调节有关，因此有人认为该激酶的预激活可能是PDGF-AA增强生长效应的一个解释。
