Ablation of biglycan attenuates cardiac hypertrophy and fibrosis after left ventricular pressure overload
Ablation of biglycan attenuates cardiac hypertrophy and fibrosis after left ventricular pressure overload
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DOI：
10.1016/j.yjmcc.2016.10.011
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发表时间：
2016-12-01
影响因子：
5
通讯作者：
Hein, Lutz
中科院分区：
文献类型：
--
作者：
Beetz, Nadine;Rommel, Carolin;Hein, Lutz
目的：Biglycan是一种小的富含亮氨酸的蛋白多糖，已被证明在稳定实验性心肌梗死后纤维化瘢痕方面发挥了重要作用。然而，在心脏压力超负荷和卸载过程中，Biglycan在心肌细胞肥大和纤维化的发生和消退中的作用仍然不清楚。因此，本研究的目的是观察Biglycan对左心室压力超负荷和卸载模型小鼠心脏重构的影响。方法和结果：由横动脉缩窄(TAC)引起的左室压力超负荷导致左心功能不全、纤维化和Biglycan表达增加。荧光和磁辅助分选心肌细胞类型显示，在TAC后，成纤维细胞群体中Biglycan的表达上调，但在心肌细胞、内皮细胞或白细胞中没有上调。短期压力超负荷(3周)后去除主动脉缩窄(RTAC)可改善野生型(WT)小鼠的心肌收缩能力和逆转心肌肥厚，但不能逆转纤维化。Biglycan消融术(KO)可促进功能恢复，但不能消除心肌纤维化。在长期TAC治疗9周后，消融Biglycan可减轻心肌肥大和纤维化的发展。在体外，Biglycan诱导新生大鼠心肌细胞肥大，并导致肥大基因程序的激活。Biglycan信号的下游调节因子包括RCAN1、ABRA和Tnfrsfl2a。这些基因在WT小鼠中表达一致，而在Biglycan KO小鼠中表达不一致。结论：左心室压力超负荷可诱导心脏成纤维细胞表达Biglycan。消融双聚糖可改善心功能，减轻长期压力超负荷后左室肥厚和纤维化。在体外，Biglycan诱导心肌细胞肥大，提示Biglycan可能作为细胞类型之间的信号分子来调节心脏重构。(C)2016爱思唯尔有限公司。保留所有权利。
Aims: Biglycan, a small leucine-rich proteoglycan, has been shown to play an important role in stabilizing fibrotic scars after experimental myocardial infarction. However, the role of biglycan in the development and regression of cardiomyocyte hypertrophy and fibrosis during cardiac pressure overload and unloading remains elusive. Thus, the aim of the present study was to assess the effect of biglycan on cardiac remodeling in a mouse model of left ventricular pressure overload and unloading.Methods and results: Left ventricular pressure overload induced by transverse aortic constriction (TAC) in mice resulted in left ventricular dysfunction, fibrosis and increased biglycan expression. Fluorescence- and magnetic-assisted sorting of cardiac cell types revealed upregulation of biglycan in the fibroblast population, but not in cardiomyocytes, endothelial cells or leukocytes after TAC. Removal of the aortic constriction (rTAC) after short-term pressure overload (3 weeks) improved cardiac contractility and reversed ventricular hypertrophy but not fibrosis in wild-type (WT) mice. Biglycan ablation (KO) enhanced functional recovery but did not resolve cardiac fibrosis. After long-term TAC for 9 weeks, ablation of biglycan attenuated the development of cardiac hypertrophy and fibrosis. In vitro, biglycan induced hypertrophy of neonatal rat cardiomyocytes and led to activation of a hypertrophic gene program. Putative downstream mediators of biglycan signaling include Rcan1, Abra and Tnfrsfl2a. These genes were concordantly induced by TAC in WT but not in biglycan KO mice.Conclusions: Left ventricular pressure overload induces biglycan expression in cardiac fibroblasts. Ablation of biglycan improves cardiac function and attenuates left ventricular hypertrophy and fibrosis after long-term pressure overload. In vitro biglycan induces hypertrophy of cardiomyocytes, suggesting that biglycan may act as a signaling molecule between cell types to modulate cardiac remodeling. (C) 2016 Elsevier Ltd. All rights reserved.