Saxena Amit, Bujak Marcin, Frunza Olga, Dobaczewski Marcin, Gonzalez-Quesada Carlos, Lu Bao, Gerard Craig, Frangogiannis Nikolaos G
The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, 1300 Morris Park Avenue Forchheimer G46B, Bronx, NY 10461, USA.
Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
Cardiovasc Res. 2014 Jul 15;103(2):217-27. doi: 10.1093/cvr/cvu138. Epub 2014 Jun 1.
The CXC chemokine CXCL10 is up-regulated in the infarcted myocardium and limits cardiac fibrosis by inhibiting growth factor-mediated fibroblast migration. CXCL10 signals by binding to its receptor CXCR3; however, recently CXCR3-independent CXCL10 actions have been suggested. Our study explores the role of CXCR3 signalling in myocardial infarction and investigates its involvement in mediating the anti-fibrotic effects of CXCL10.
Wild-type and CXCR3 null mice underwent reperfused infarction protocols. CXCL10 was markedly induced in the infarct; in contrast, expression of the other two CXCR3 ligands, CXCL9 and CXCL11 was extremely low. CXCR3 loss did not affect scar size, geometric ventricular remodelling, collagen deposition, and systolic dysfunction of the infarcted heart. CXCR3 null mice had increased peak neutrophil recruitment and delayed myofibroblast infiltration in the infarcted heart, but exhibited comparable myocardial expression of pro-inflammatory cytokines and chemokines. In vitro, CXCL10 did not modulate Transforming Growth Factor (TGF)-β signalling, but inhibited basic fibroblast growth factor (bFGF)-induced cardiac fibroblast migration in both wild-type and CXCR3 null cells. Treatment of fibroblasts with heparinase and chondroitinase to cleave glycosaminoglycan chains abrogated the inhibitory effects of CXCL10 on cell migration.
CXCR3 signalling does not critically regulate cardiac remodelling and dysfunction following myocardial infarction. The anti-fibrotic effects of CXCL10 in the healing infarct and in isolated cardiac fibroblasts are CXCR3-independent and may be mediated through proteoglycan signalling. Thus, administration of CXCR3-defective forms of CXCL10 may be an effective anti-fibrotic strategy in the remodelling myocardium without activating a potentially injurious, CXCR3-driven T cell response.
CXC趋化因子CXCL10在梗死心肌中上调，并通过抑制生长因子介导的成纤维细胞迁移来限制心脏纤维化。CXCL10通过与其受体CXCR3结合来传递信号；然而，最近有人提出了CXCL10不依赖CXCR3的作用。我们的研究探讨了CXCR3信号传导在心肌梗死中的作用，并研究了其在介导CXCL10的抗纤维化作用中的参与情况。
野生型和CXCR3基因敲除小鼠接受了再灌注梗死方案。CXCL10在梗死灶中明显诱导表达；相比之下，另外两种CXCR3配体CXCL9和CXCL11的表达极低。CXCR3缺失不影响梗死心脏的瘢痕大小、心室几何重塑、胶原沉积和收缩功能障碍。CXCR3基因敲除小鼠梗死心脏中的中性粒细胞募集峰值增加，成肌纤维细胞浸润延迟，但促炎细胞因子和趋化因子的心肌表达相当。在体外，CXCL10不调节转化生长因子（TGF）-β信号传导，但在野生型和CXCR3基因敲除细胞中均抑制碱性成纤维细胞生长因子（bFGF）诱导的心脏成纤维细胞迁移。用肝素酶和软骨素酶处理成纤维细胞以切割糖胺聚糖链，消除了CXCL10对细胞迁移的抑制作用。
CXCR3信号传导对心肌梗死后的心脏重塑和功能障碍没有关键调节作用。CXCL10在愈合梗死灶和分离的心脏成纤维细胞中的抗纤维化作用不依赖CXCR3，可能通过蛋白聚糖信号传导介导。因此，给予CXCR3缺陷型的CXCL10可能是重塑心肌中一种有效的抗纤维化策略，而不会激活潜在有害的、由CXCR3驱动的T细胞反应。
