Division of Geriatrics, Gerontology and Palliative Medicine, Department of Medicine, The University of Texas Health Science Center at San Antonio, USA.
Am J Physiol Heart Circ Physiol. 2011 Apr;300(4):H1418-26. doi: 10.1152/ajpheart.01002.2010. Epub 2011 Feb 4.
Post-myocardial infarction (MI), chemokine homing of inflammatory cells into the injured left ventricle (LV) regulates ventricular remodeling, in part by stimulating the extracellular matrix response. The CC chemokine receptor 5 (CCR5) is a key chemokine receptor expressed on macrophages, and CCR5 ligands are highly upregulated post-MI. We hypothesized that deletion of CCR5 would attenuate adverse remodeling by decreasing inflammatory cell recruitment. Accordingly, we examined LV function, macrophage recruitment and activation, and collagen content in wild-type (WT, n = 25) and CCR5 null (n = 33) mice at 7 days post-MI. Both groups had similar infarct sizes (44 ± 2% in WT and 42 ± 2% in CCR5 null; P = 0.37). However, the LV remodeling index (end diastolic volume/LV mass) increased to a larger extent in CCR5 null (1.28 ± 0.08 μl/mg for CCR5 null and 1.02 ± 0.06 μl/mg for WT; P < 0.05). Although numbers of infiltrated macrophages were similar in WT and CCR5 null mice, CCR5-deficient macrophages isolated from the infarct zone displayed >50% decrease in gene expression levels of proinflammatory activation markers (interleukin-1β, interleukin-6, and tumor necrosis factor-α), as well as anti-inflammatory activation markers (arginase 1, CD163, mannose receptor, and transforming growth factor-β1) compared with WT (all P < 0.05). Concomitant with the reduced macrophage activation, heat shock protein-47 and collagen type I precursor levels in the infarct region decreased in the CCR5 null (1.2 ± 0.3 units in the CCR5 null and 2.3 ± 0.4 units in the WT; P < 0.05), while collagen fragments increased (88.3 ± 5.9 units in the CCR5 null and 32.7 ± 8.5 units in the WT; P < 0.05). We conclude that CCR5 deletion impairs LV remodeling by hindering macrophage activation, which stimulates an imbalance in collagen metabolism and increases the remodeling index.
心肌梗死后（MI），炎症细胞向受损左心室（LV）的趋化因子归巢调节心室重构，部分通过刺激细胞外基质反应。趋化因子受体 5（CCR5）是巨噬细胞上表达的关键趋化因子受体，CCR5 配体在 MI 后高度上调。我们假设 CCR5 的缺失会通过减少炎症细胞募集来减轻不良重构。因此，我们在 MI 后 7 天检查了野生型（WT，n=25）和 CCR5 缺失（n=33）小鼠的 LV 功能、巨噬细胞募集和激活以及胶原蛋白含量。两组的梗死面积相似（WT 为 44±2%，CCR5 缺失为 42±2%；P=0.37）。然而，CCR5 缺失组的 LV 重构指数（舒张末期容积/LV 质量）增加幅度更大（CCR5 缺失组为 1.28±0.08 μl/mg，WT 组为 1.02±0.06 μl/mg；P<0.05）。尽管 WT 和 CCR5 缺失小鼠的浸润巨噬细胞数量相似，但从梗死区分离的 CCR5 缺陷型巨噬细胞的促炎激活标志物（白细胞介素-1β、白细胞介素-6 和肿瘤坏死因子-α）和抗炎激活标志物（精氨酸酶 1、CD163、甘露糖受体和转化生长因子-β1）的基因表达水平下降了>50%（均 P<0.05）。与巨噬细胞激活减少同时发生的是，CCR5 缺失组梗死区的热休克蛋白 47 和胶原 I 前体水平降低（CCR5 缺失组为 1.2±0.3 单位，WT 组为 2.3±0.4 单位；P<0.05），而胶原片段增加（CCR5 缺失组为 88.3±5.9 单位，WT 组为 32.7±8.5 单位；P<0.05）。我们得出结论，CCR5 缺失通过阻碍巨噬细胞激活来损害 LV 重构，从而刺激胶原蛋白代谢失衡并增加重构指数。
