Yu Qianli, Watson Ronald R, Marchalonis John J, Larson Douglas F
Department of Medical Pharmacology, School of Medicine, Univ. of Arizona, 1501 N. Campbell Ave., Tucson, AZ 85724, USA.
Am J Physiol Heart Circ Physiol. 2005 Aug;289(2):H643-51. doi: 10.1152/ajpheart.00073.2005.
The induction of T helper (TH) lymphocytes by distinct TH ligands results in a differentiation to TH1/TH2 subsets based on their unique pattern of cytokine secretion and effector functions. We hypothesized that the relative proportion of TH1/TH2 directly relates to cardiac fibroblast (CF) function and thereby cardiac extracellular matrix (ECM) composition and cardiac diastolic function in the absence of injury or altered wall stress. We compared the effect of selective TH1 with TH2 inducers on cardiac gene expression, ECM composition, and diastolic function in C57BL/J mice. Twelve weeks after immune modulation, the left ventricular stiffness (beta) was significantly increased in the TH1 group and decreased in the TH2 group (P < 0.01). The TH2 group also demonstrated significantly increased end-diastolic and end-systolic volumes (P < 0.01). Cardiac gene expression patterns for pro-matrix metalloproteinase (MMP)-9 and -13 were increased by greater than fivefold in the TH2 group and significantly decreased in the TH1 group (P < 0.05). The total cardiac collagen and cross-linked collagen were significantly increased in the TH1 group and decreased in the TH2 group (P < 0.01). Coculturing lymphocytes harvested from the treated mice with naive primary CF demonstrated a direct control of the lymphocytes on CF pro-collagen, pro-MMP gene expression, and MMP activity. These results suggest that the TH phenotype differentially affects diastolic function through modulating CF pro-collagen and pro-MMP gene expression, MMP activity, and cardiac collagen cross-linking, resulting in altered ECM composition. Thus modulation of TH lymphocyte function could promote adaptive remodeling in heart failure and postmyocardial infarction.
不同的辅助性T（TH）淋巴细胞配体诱导TH淋巴细胞，会根据其独特的细胞因子分泌模式和效应功能分化为TH1/TH2亚群。我们推测，在没有损伤或壁应力改变的情况下，TH1/TH2的相对比例直接关系到心脏成纤维细胞（CF）的功能，进而关系到心脏细胞外基质（ECM）的组成和心脏舒张功能。我们比较了选择性TH1诱导剂与TH2诱导剂对C57BL/J小鼠心脏基因表达、ECM组成和舒张功能的影响。免疫调节12周后，TH1组左心室僵硬度（β）显著增加，TH2组则降低（P<0.01）。TH2组舒张末期和收缩末期容积也显著增加（P<0.01）。TH2组中促基质金属蛋白酶（MMP）-9和-13的心脏基因表达模式增加了五倍以上，而TH1组则显著降低（P<0.05）。TH1组心脏总胶原蛋白和交联胶原蛋白显著增加，TH2组则减少（P<0.01）。将从经处理的小鼠中收获的淋巴细胞与未接触过抗原的原代CF共培养，结果表明淋巴细胞对CF前胶原蛋白、前MMP基因表达和MMP活性具有直接调控作用。这些结果表明，TH表型通过调节CF前胶原蛋白和前MMP基因表达、MMP活性以及心脏胶原蛋白交联，以不同方式影响舒张功能，从而导致ECM组成改变。因此，调节TH淋巴细胞功能可能促进心力衰竭和心肌梗死后的适应性重塑。
