| Background: It is widely accepted that extensive myocardial infarction (MI) could induce the process of ventricular remodeling. SDF-1 is expressed in bone marrow, heart, skeletal muscle and brain. CXCR4, the receptor of SDF-1, is expressed in hematopoietic stem cell (HSCs), endothelial pregenitor cell (EPC) and Mesenchyme stem cells (MSCs). CXCR4~+ stem cells can be anchored in bone marrow by binding to SDF-1. The expression of SDF-1 was up-regulated in ischemia tissue, and CXCR4~+ stem cells can recruit to ischemia tissue along the concentration gradient. AMD3100 was known as a specific antagonist of CXCR4, which can inhibit the interaction between SDF-1 and CXCR4, and promote the mobilization of stem cells from bone marrow into peripheral blood. However, it is not clear that whether the mobilized stem cells could homing to ischemia region, and whether the stem cells mobilized by AMD3100 could recruit to ischemia zoon via the non-CXCR4 pathway, as well as whether they could promote the tissue repair in infarcted region by paracrine effect.Objective: To investigate the effect of AMD3100 on tissue repair and ventricular remodeling as well as the possible mechanism, we evaluated histopathological and gelatin zymography changes in infarcted area dynamically in MI.Methods: MI was induced in male Wistar rats (8-10 weeks old) by permanent coronary ligation. The survival rats were randomly divided into sham group (n=10), Mi-saline group (n=10) and AMD3100 treatment group (MI-A group, n=21). Two time points of drug administration were examined: AMD3100 was injected 1 h (Immediate AMD3100, MI-IA) and 24 h post-MI (Delayed-AMD3100, MI-DA). Rats were sacrificed at 7 days and 3 months after MI respectively. Index of expansion and infarct size were examined by picrosirius staining. Collagen volume fraction (CVF) and proportion of collagen fiber were qantified by picrosirius staining plus polarized microscopy. Arterioles density and capillary density in infarcted region were evaluated by anti-α-SMA and anti-vWF immunofluorescent staining, respectively. Cardiomyocyte cross-sectional area (CSA) in non-infarct region was assessed by WGA fluorescent staining. The activities of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) within infarcted region at 7 days and 3 months after MI were determined by gelatin zymography.Result: 1. Histopathology: (1) The index of left ventricular weight was not significantly different between each group (P＞0.05). (2) Compared with 7d-group, CSA (713.41±28.29μm~2 vs. 387.10±22.85μm~2, P＜0.05) was increased in MI-saline-3m group; free ventricular wall thickness had decreasing tendency in MI-saline-3m group (P=0.075). Compared with Mi-saline group, free ventricular wall thickness was notablely decreased in MI-DA-7d group; Compared with MI-saline-3m group, CSA (465.16±39.66μm~2 and 441.66±20.25μm~2 vs. 713.41±28.29μm~2, P＜0.05) and infarct size (27.44±1.60% and 32.49±3.53% vs. 48.04±3.69%, P＜0.05) was decreased in MI-IA-3m group and MI-DA-3m group (P＜0.05). (3) Compared with MI-saline-7d group and MI-DA-7d group, the proportion of collagen fiber had increasing tendency in MI-IA-7d group (P=0.126andP=0.204). Compared with MI-saline-3m group, the proportion of collagen fiber was increased in MI-IA-3m group (P＜0.05); the proportion of collagen fiber had increasing tendency in MI-DA-3m group (P=0.168). (4) Compared with 7d group for the same group, arteriole density (25.41±2.62/mm~2 vs. 14.31±1.58/mm~2, P＜0.05) was increased in MI-DA-3m group. Compared with MI-saline-3m group, arteriole density (25.41±2.62/mm~2 and22.42±4.19/mm~2 vs. 12.32±3.93/mm~2) was increased in MI-DA-3m group and MI-IA-3m group (P＜0.05). (5) Compared with MI-saline-7d group, capillary density (41.40±1.04/mm~2 and 75.61±3.84/mm~2 vs. 26.37±1.86/mm~2, P＜0.05) was increased in MI-DA-7d group and MI-IA-7d group. Compared with MI-saline-3m group, capillary density (59.77±5.35/mm~2 and 50.33±1.07/mm~2 vs. 27.46±1.13/mm~2, P＜0.05) was increased in MI-DA-3m group and MI-IA-3m group. Compared with MI-IA-7d group, capillary density (41.40±1.04/mm~2 vs. 75.61±3.84/mm~2, P＜0.05) was reduced in MI-DA-7d group.2. Gelatin zymography analysis: Compared with MI-DA-7d group, the protein activity of MMP-9 was increased in MI-IA-7d group (P＜0.05). Compared with MI-saline-3m group, the protein activity of MMP-2 was markly increased in MI-DA group and MI-IA group (P＜0.05).Conclusion: Our experiment demonstrated that AMD3100 can increase free ventricular wall thickness, decrease the CSA and infarct size, and improve ventricular remodeling after MI. The possible mechanism may be through non-CXCR4 pathway of recruited stem cells to accelerate collagen deposition and maturation, and promote neovascularization.
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