A study for prevention of ventricular remodeling after myocardial infarction by regulating functions of tenascin-C.

腱生蛋白-C（Tenascin-C，TN-C）是一种细胞外基质糖蛋白，在病理性心脏中短暂出现，在组织重塑中起重要作用。为了阐明其在急性心肌梗死（AMI）后心室重构中的作用，我们测定了AMI患者的TN-C水平，并与心功能和患者结局进行了比较。血清TN-C水平在AMI后急性期显著升高，并在5天内达到高峰。左心室（LV）重构组的峰值TN-C水平显著高于非重构组。高TN-C水平的AMI患者发生心源性死亡、非致死性AMI和因充血性心力衰竭住院的风险更高。接下来，我们使用TN-C敲除（KO）小鼠检测TN-C缺失对AMI后心室重构的影响，并与野生型（WT）小鼠进行比较。尽管到第28天KO和WT之间的存活率没有检测到显著差异，但KO小鼠表现出显著更少的LV腔扩张，更少的左心室舒张末期压力升高，以及改善的缩短分数和射血分数。在组织学上，KO小鼠中残留心肌中的间质纤维化减少。此外，我们使用基于Cre/loxP重组的小鼠遗传系统研究了心脏特异性TN-C过表达小鼠损伤后的心肌修复。TN-C过度表达时，心肌成纤维细胞的募集和心肌纤维化均较WT组加快。虽然TN-C对心室重构的影响不是简单的，而是双向的，但TN-C的过度和持续增加可能导致梗死室壁的不适当重建，并可能成为潜在的治疗靶点。

Tenascin-C (TN-C), an extracellular matrix glycoprotein, transiently appears in the pathologic heart, playing important roles in tissue remodeling. To elucidate its role in ventricular remodeling after acute myocardial infarction(AMI), we measured TN-C levels in patients with AMI and compared with cardiac function and patient outcomes. Serum TN-C levels were significantly elevated during the acute stage after AMI and peaked within 5 days. Peak TN-C levels were significantly higher in the left ventricular (LV) remodeling group than the non-remodeling group. AMI patients with high TN-C levels were at much higher risk of cardiac death, non fatal AMI, and hospitalization for congestive heart failure. Next, we examined the effects of deletion of TN-C on post-AMI ventricular remodeling using TN-C knockout(KO) mice and compared with those of the wild type(WT). Although no significant difference was detected in survival rate between KO and WT by day 28, The KO mice exerted significantly less LV cavity dilatation, less elevation of endodiastolic left ventricular pressure, and improved fractional shortening and ejection fraction. Histologically, interstitial fibrosis in the residual myocardium is reduced in KO mice. Furthermore, we examined myocardial repair after injury in heart specific TN-C over-expressing mice using a mouse genetic system based on Cre/loxP recombination. With excess expression of TN-C, recruitment of myofibroblasts and myocardial fibrosis was accelerated to compared with that in WT. Although the effects of TN-C on ventricular remodeling are not simple, but rather are bidirectional, it was suggested that excessive and sustained increments of TN-C could inappropriate reconstruction of infarcted ventricular wall and a potential therapeutic target.