Pathophysiological role of cardiotrophin-1 in heart failure

心肌营养因子-1 （Cardiotrophin-1, CT-1）是一种有效的细胞因子，它通过gp130信号传导刺激心肌细胞中肌合成单位的串联组装，导致心肌细胞肥大。我们检测了CT-1和gp130系统在两种充血性心力衰竭大鼠模型中的作用。首先，我们检测了CT-1和gp130在大鼠心肌梗死模型中的表达。超声心动图证实进行性左心室扩张和存活心肌肥厚不充分。RT-PCR密度分析显示，与假手术大鼠相比，在梗死后1、3、7、14、28和56天，双心室CT-1和gp130 mRNA水平显著升高。Western blot检测CT-1和gp130蛋白水平均较假手术大鼠显著升高，在上述三个区域均在急性期达到峰值，随后下降。免疫组化染色显示心肌细胞和成纤维细胞样细胞中存在CT-1、More和gp130免疫反应。因此，增强的CT-1和gp130系统似乎在心肌梗死后心室重构中起重要作用。其次，我们在高盐饮食的达尔盐敏感（DS）大鼠中检测了CT-1和gp130的表达，这些大鼠表现出从左心室肥厚（LVH）到充血性心力衰竭（CHF）的明显转变。与LVH期和年龄匹配的达尔耐盐（DR）大鼠相比，CHF期CT-1表达水平显著升高（每组n=6）。与年龄匹配的DR大鼠相比，11、17周时DS大鼠gp130 mRNA和蛋白水平显著升高。17周时DS大鼠离体肌细胞长度在4组大鼠中最长。CHF期DS大鼠左室舒张末期尺寸（LVDd）明显升高。CT-1蛋白水平与LVDd有显著相关性。CT-1可能在大鼠高血压模型中LVH向CHF过渡过程中的心室重构中发挥作用。这些在两种心力衰竭模型中的发现强烈表明，CT-1在心力衰竭的心室扩张中起着核心作用。少

Cardiotrophin-1 (CT-1) is a potent cytokine that stimulates the assembly of sarcomeric units in series in cardiomyocytes through gp130 signaling, resulting in myocardial cell hypertrophy. We examined the role of CT-1 and gp130 system in the two rat models of congestive heart failure. First, we examined the expression of CT-1 and gp130 in a rat model of myocardial infarction. Progressive left ventricular dilatation and inadequate hypertrophy of the surviving myocardium were confirmed by echocardiography. The densitometric analysis of RT-PCR revealed a significant increase in CT-1 and gp130 mRNA levels compared with those of the sham-operated rats at 1, 3, 7, 14, 28 and 56 days post-infarct in both ventricles. The protein levels of CT-1 and gp130, determined by Western blot analysis, were significantly increased compared to those of sham-operated rats, and peaked in the acute stage and declned thereafter in the three regions described above. Immunohistochemical staining showed that CT-1 … More and gp130-immunoreactivities were detected in cardiomyocytes and fibroblast-like cells. An augmented CT-1 and gp130 system thus seems to play an important role during ventricular remodeling after myocardial infarction. Secondly, we examined the expression of CT-1 and gp130 in Dahl salt-sensitive (DS) rats with a high-salt diet which showed a distinct transition from left ventricular hypertrophy (LVH) to congestive heart failure (CHF). The expression levels of CT-1 were significantly increased at the CHF stage compared with the LVH stage and age-matched Dahl salt-resistant (DR) rats (n=6 for each group). gp130 mRNA and protein levels DS rats at 11 and 17 weeks were significantly increased compared with age-matched DR rats. The isolated myocyte length of DS rats at 17 weeks was the longest among the 4 groups of rats. The left ventricular end-diastolic dimension (LVDd) of DS rats was significantly increased at the CHF stage. There was a significant correlation between the CT-1 protein level and LVDd. CT-1 may play a role in ventricular remodeling during transition from LVH to CHF in the rat hypertensive model. These findings in the two heart failure models strongly suggest that CT-1 plays a central role in the ventricular dilatation in heart failure. Less