Syndecan-4 Prevents Cardiac Rupture and Dysfunction After Myocardial Infarction
Syndecan-4 Prevents Cardiac Rupture and Dysfunction After Myocardial Infarction
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DOI：
10.1161/circresaha.110.235689
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发表时间：
2011-05-27
影响因子：
20.1
通讯作者：
Uede, Toshimitsu
中科院分区：
文献类型：
--
作者：
Matsui, Yutaka;Ikesue, Masahiro;Uede, Toshimitsu
基本原理：Syndecan-4（Syn 4）是一种细胞表面硫酸乙酰肝素蛋白多糖，在心肌梗死（MI）后梗死区域被检测到，但其功能意义尚未阐明。目的：我们研究Syn 4是否以及如何调节MI后心脏愈合过程。虽然Syn 4缺陷（Syn 4（-/-））小鼠的心脏在形态和功能上是正常的，但Syn 4（-/-）小鼠表现出心脏功能受损和MI后心脏破裂导致的死亡率增加。Syn 4（-/-）小鼠心脏破裂与MI早期炎症反应减少和肉芽组织形成受损相关，如MI后梗死区白细胞、成纤维细胞、肌成纤维细胞、巨噬细胞和毛细血管数量减少以及细胞外基质蛋白沉积减少沿着。转化生长因子β 1依赖性细胞信号被保留，而细胞迁移，纤连蛋白诱导的细胞信号，并分化成肌成纤维细胞在Syn 4（-/-）心脏成纤维细胞缺陷。我们还发现Syn 4参与碱性成纤维细胞生长因子依赖的内皮细胞信号传导、细胞增殖和管形成。最后，在心肌梗死前过度表达脱落形式的Syn 4通过其作为内源性Syn 4信号传导的显性负抑制剂的作用导致心脏破裂导致死亡率增加，这表明Syn 4信号传导在心肌梗死中的保护作用。这些结果表明，Syn 4在炎症反应和肉芽组织形成中起重要作用，从而防止MI后心脏破裂和功能障碍。(Circ Res. 2011; 108：1328-1339）。
Rationale: Syndecan-4 (Syn4), a cell-surface heparan sulfate proteoglycan, has been detected in the infarct region after myocardial infarction (MI), but its functional significance has not been elucidated.Objective: We examined whether and how Syn4 regulates the cardiac healing process after MI.Methods and Results: Although the heart in Syn4-deficient (Syn4(-/-)) mice was morphologically and functionally normal, Syn4(-/-) mice exhibited impaired heart function and increased mortality rate as a result of cardiac ruptures after MI. Cardiac ruptures in Syn4(-/-) mice were associated with reduced inflammatory reaction and impaired granulation tissue formation during the early phase of MI, as evidenced by reduced numbers of leukocytes, fibroblasts, myofibroblasts, macrophages, and capillary vessels, along with reduced extracellular matrix protein deposition in the infarct region after MI. Transforming growth factor-beta 1-dependent cell signaling was preserved, whereas cell migration, fibronectin-induced cell signaling, and differentiation into myofibroblasts were defective in Syn4(-/-) cardiac fibroblasts. We also found that Syn4 was involved in basic fibroblast growth factor-dependent endothelial cell signaling, cell proliferation, and tube formation. Finally, overexpression of the shed form of Syn4 before MI creation led to an increase in mortality due to cardiac rupture via its action as a dominant-negative inhibitor of endogenous Syn4 signaling, which suggested a protective role of Syn4 signaling in MI.Conclusions: These results suggest that Syn4 plays an important role in the inflammatory response and granulation tissue formation, thereby preventing cardiac rupture and dysfunction after MI. (Circ Res. 2011; 108: 1328-1339.)