Induction of the CXC chemokine interferon-gamma-inducible protein 10 regulates the reparative response following myocardial infarction.
Induction of the CXC chemokine interferon-gamma-inducible protein 10 regulates the reparative response following myocardial infarction.
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DOI：
10.1161/circresaha.109.199471
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发表时间：
2009-11-06
影响因子：
20.1
通讯作者：
Frangogiannis NG
中科院分区：
文献类型：
--
作者：
Bujak M;Dobaczewski M;Gonzalez-Quesada C;Xia Y;Leucker T;Zymek P;Veeranna V;Tager AM;Luster AD;Frangogiannis NG
干扰素-γ-诱导蛋白（IP）-10/CXCL10是一种血管生成抑制和抗纤维化趋化因子，在T细胞运输中起重要作用，在心肌梗死中被显著诱导，并可调节修复反应。研究IP-10在心脏修复和重构中的作用。我们研究了IP-10 null和WT小鼠进行再灌注梗死协议的心脏修复，并检查了IP-10对心脏成纤维细胞功能的影响。IP-10缺陷和WT动物具有相当的急性梗死面积。然而，IP-10的缺乏导致细胞过度的早期修复反应和瘢痕的延迟收缩。IP-10 −/−阻断的心脏表现出加重的早期扩张，随后在与收缩功能障碍相关的梗死成熟过程中快速壁变薄。虽然IP-10 null和WT小鼠具有相当的细胞因子表达，IP-10的缺乏与梗死细胞内容物的显著改变相关。与WT梗死相比，IP-10 −/−梗死具有更强烈的CD 45+白细胞、Mac-2+巨噬细胞和α-平滑肌肌动蛋白（α-SMA）+肌成纤维细胞浸润，但表现出表达CXCR 3（IP-10受体）的白细胞、T淋巴细胞和α-SMA+细胞亚群的募集减少。IP-10不调节心脏成纤维细胞增殖和凋亡，但显著抑制碱性成纤维细胞生长因子诱导的成纤维细胞迁移。此外，IP-10增强成纤维细胞填充的胶原晶格中生长因子介导的伤口收缩。内源性IP-10是调节愈合梗死的细胞组成并促进伤口收缩、减弱不良重塑的重要抑制信号。IP-10介导的作用可能至少部分是由于对成纤维细胞迁移和功能的直接影响。
Interferon-γ-inducible protein (IP)-10/CXCL10, an angiostatic and antifibrotic chemokine with an important role in T cell trafficking, is markedly induced in myocardial infarcts, and may regulate the reparative response. To study the role of IP-10 in cardiac repair and remodeling. We studied cardiac repair in IP-10 null and WT mice undergoing reperfused infarction protocols and examined the effects of IP-10 on cardiac fibroblast function. IP-10 deficient and WT animals had comparable acute infarct size. However, IP-10 absence resulted in a hypercellular early reparative response and delayed contraction of the scar. Infarcted IP-10 −/− hearts exhibited accentuated early dilation, followed by rapid wall thinning during infarct maturation associated with systolic dysfunction. Although IP-10 null and WT mice had comparable cytokine expression, IP-10 absence was associated with marked alterations in the cellular content of the infarct. IP-10 −/− infarcts had more intense infiltration with CD45+ leukocytes, Mac-2+ macrophages and α-smooth muscle actin (α-SMA)+ myofibroblasts than WT infarcts but exhibited reduced recruitment of the subpopulations of leukocytes, T lymphocytes and α-SMA+ cells that expressed CXCR3, the IP-10 receptor. IP-10 did not modulate cardiac fibroblast proliferation and apoptosis, but significantly inhibited basic Fibroblast Growth Factor-induced fibroblast migration. In addition, IP-10 enhanced growth factor-mediated wound contraction in fibroblast-populated collagen lattices. Endogenous IP-10 is an essential inhibitory signal that regulates the cellular composition of the healing infarct and promotes wound contraction, attenuating adverse remodeling. IP-10-mediated actions may be due, at least in part, to direct effects on fibroblast migration and function.