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。我们研究了肥大细胞（肥大细胞增殖和分化的重要因子）、干细胞因子（SCF）及其受体c-kit在人和小鼠心力衰竭动物模型中的作用。心力衰竭患者肥大细胞数量增加，SCF表达增加。我们发现，在脑心肌炎病毒（EMCV）引起的小鼠心力衰竭模型心脏中，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显著升高。我们发现，使用两种肥大细胞缺陷小鼠，心脏中肥大细胞的缺乏可以保护小鼠免受急性EMCV心肌炎的致死性，并且与对照组小鼠相比，肥大细胞重构缺陷小鼠的心肌炎恶化。肥大细胞蛋白酶基因表达在病毒性心肌炎急性期上调，在心衰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生一致，并与肥大细胞切酶和基质金属蛋白酶(MMP)-9基因表达上调相关。这些发现表明肥大细胞参与急性炎症反应和与急性病毒性心肌炎相关的心室重构过程的开始。

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.