Syndecan-4 Protects the Heart From the Profibrotic Effects of Thrombin-Cleaved Osteopontin
Syndecan-4 Protects the Heart From the Profibrotic Effects of Thrombin-Cleaved Osteopontin
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DOI：
10.1161/jaha.119.013518
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发表时间：
2020-02-04
影响因子：
5.4
通讯作者：
Christensen, Geir
中科院分区：
文献类型：
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作者：
Herum, Kate M.;Romaine, Andreas;Christensen, Geir
背景高血压或瓣膜狭窄患者会出现心脏压力超负荷，并由于激活的心脏成纤维细胞过度产生细胞外基质而导致心脏纤维化。这最初为心脏提供了必要的机械支持，但最终会损害功能。骨桥蛋白与纤维化有关，然而，其潜在的信号传导机制还不清楚。在此，我们研究了凝血酶裂解的骨桥蛋白对心脏纤维化的影响，并探讨了syndecan-4在调节骨桥蛋白裂解中的作用。方法和结果骨桥蛋白上调和凝血酶在压力超负荷的小鼠心脏切割主动脉束带。接受晶体液治疗的主动脉瓣狭窄患者血浆中的切割骨桥蛋白高于血液心脏停搏液，这可能是因为肝素诱导的凝血酶抑制较少。切割的骨桥蛋白和凝血酶切割后暴露的特异性骨桥蛋白肽序列RGDSLAYGLR均诱导心脏成纤维细胞中的胶原蛋白产生。与骨桥蛋白一样，硫酸乙酰肝素蛋白多糖多配体蛋白聚糖-4在主动脉缩窄后上调。与骨桥蛋白切割位点中的硫酸乙酰肝素结合结构域一致，发现多配体蛋白聚糖-4与左心室和心脏成纤维细胞中的骨桥蛋白结合，并保护骨桥蛋白免受凝血酶切割。脱落的syndecan-4的细胞外部分是更突出的后期重塑phase，在这个时间水平的裂解骨桥蛋白increased. ConclusionsThrombin裂解骨桥蛋白诱导心脏成纤维细胞胶原蛋白的生产。多配体蛋白聚糖-4保护骨桥蛋白免受凝血酶切割，但当多配体蛋白聚糖-4在重塑的后期脱落时，这种保护作用丧失，从而导致心脏纤维化的进展。
BackgroundPressure overload of the heart occurs in patients with hypertension or valvular stenosis and induces cardiac fibrosis because of excessive production of extracellular matrix by activated cardiac fibroblasts. This initially provides essential mechanical support to the heart, but eventually compromises function. Osteopontin is associated with fibrosis; however, the underlying signaling mechanisms are not well understood. Herein, we examine the effect of thrombin-cleaved osteopontin on fibrosis in the heart and explore the role of syndecan-4 in regulating cleavage of osteopontin.Methods and ResultsOsteopontin was upregulated and cleaved by thrombin in the pressure-overloaded heart of mice subjected to aortic banding. Cleaved osteopontin was higher in plasma from patients with aortic stenosis receiving crystalloid compared with blood cardioplegia, likely because of less heparin-induced inhibition of thrombin. Cleaved osteopontin and the specific osteopontin peptide sequence RGDSLAYGLR that is exposed after thrombin cleavage both induced collagen production in cardiac fibroblasts. Like osteopontin, the heparan sulfate proteoglycan syndecan-4 was upregulated after aortic banding. Consistent with a heparan sulfate binding domain in the osteopontin cleavage site, syndecan-4 was found to bind to osteopontin in left ventricles and cardiac fibroblasts and protected osteopontin from cleavage by thrombin. Shedding of the extracellular part of syndecan-4 was more prominent at later remodeling phases, at which time levels of cleaved osteopontin were increased.ConclusionsThrombin-cleaved osteopontin induces collagen production by cardiac fibroblasts. Syndecan-4 protects osteopontin from cleavage by thrombin, but this protection is lost when syndecan-4 is shed in later phases of remodeling, contributing to progression of cardiac fibrosis.