Roles of mast cells, stem cell factor and c-kit in heart failure

肥大细胞是多种细胞因子、化学介质和蛋白酶的强大生产者，在心力衰竭的发病机制中起主要作用。本研究探讨了肥大细胞、干细胞因子（stem cell factor，SCF）及其受体c-kit在人心力衰竭和小鼠心力衰竭动物模型中的作用。心力衰竭患者心脏中肥大细胞数量和SCF表达增加，我们发现脑心肌炎病毒（EMCV）所致心力衰竭小鼠模型心脏中干细胞因子（SCF）、肥大细胞生长因子（肥大细胞生长因子）的表达和肥大细胞密度均显著增加。我们发现，使用两个品系的肥大细胞缺陷小鼠，心脏中的肥大细胞的缺乏保护小鼠免于因急性EMCV心肌炎而致死，并且与对照小鼠相比，肥大细胞向其缺陷小鼠的重建使心肌炎恶化。肥大细胞蛋白酶的基因表达在病毒性心肌炎的急性期上调，并且在心力衰竭的亚急性期进一步升高。它们的激活与心肌坏死和纤维化的发展相一致，并与肥大细胞糜酶和基质金属蛋白酶（MMP）-9基因表达的上调相关。这些结果表明，肥大细胞参与急性炎症反应，并在心室重塑过程的开始与急性病毒性心肌炎。

Mast cells are powerful producers of multiple cytokines, chemical mediators, and proteases, playing a principal role in the pathogenesis of heart failure. We investigated the roles of mast cells, an essential factor for proliferation and differentiation of mast cells, stem cell factor (SCF) and its receptor c-kit in heart failure in human and an animal model in mice. Number of mast cells, and the expression of SCF are increased in patients with heart failure.We found that the expression of stem cell factor (SCF), mast cell growth factor, and mast cell density were significantly increased in the heart of murine heart failure model due to encephalomyocarditis virus (EMCV) myocarditis. We showed that using two strains of mast cell deficient mice, the lack of mast cells in the heart protected mice against lethality due to acute EMCV myocarditis, and that the reconstitution of mast cells to their deficient mice deteriorated myocarditis compared with their control mice.The gene expressions of mast cell proteases were upregulated in the acute phase of viral myocarditis, and rose further in the subacute phase of heart failure. Their activation coincided with the development of myocardial necrosis and fibrosis, and correlated with the upregulation of the gene expressions of mast cell chymase and matrix metalloproteinase (MMP)-9. These findings suggest that mast cells participate in the acute inflammatory reaction and in the beginning of the ventricular remodeling process associated with acute viral myocarditis.