Objectives: Postconditioning attenuates inflammation and fibrosis in myocardial infarction (MI). Aim of this study was to investigate whether postconditioning with the CpG-containing TLR9-ligand 1668-thioate (CpG) can modulate inflammation and remodeling in reperfused murine MI. Methods: Thirty min. LAD-occlusion was conducted in 12 weeks old C57BL/6 mice. Mice were treated with CpG i.p. 5 min. before reperfusion. Control group received PBS; sham group did not undergo ischemia. M-mode echocardiography (3, 7 and 28 days) and Millar^® left ventricular (LV) catheter were performed (7 and 28 days) before hearts where excised and harvested for immunohistochemical (6, 24 hrs, 3, 7, 28 days), gene expression (6, 24 hrs, 3 days; Taqman^® RT-qPCR), protein and FACS analysis (24 hrs, 3 days). Results: Mice treated with CpG showed significantly better LV function after 7- and 28-days reperfusion. Protein- and mRNA-expression of pro- and anti-inflammatory cytokines were significantly induced after CpG-treatment. Histology revealed fewer macrophages in CpG-mice after 24 hrs, confirmed by FACS-analysis with decrease in both, classically M1- and alternative M2a-monocytes. CpG-treatment reduced apoptosis and cardiomyocyte-loss and was associated with induction of adaptive mechanisms, e.g. of heme-oxigenase-1 and b-/a-MHC ratio. Pro-fibrotic markers col-Ia and -III induction was abrogated in CpG-mice, accompanied by fewer myofibroblasts. This lead to formation of a smaller scar. Differential MMP/TIMP-expression contributed to attenuated remodeling in CpG, resulting in preserved cardiac function in a TLR1 and -9 dependant manner. Conclusion: Our study suggests a cardioprotective mechanism of CpG-postconditioning, involving TLR-driven modulation of inflammation. This is followed by attenuated remodeling and preserved LV-function.

中文翻译：

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再灌注心肌梗死后的CpG后处理与炎症调节，凋亡减少和左心室功能改善有关。

目的：后处理可减轻心肌梗死（MI）的炎症和纤维化。这项研究的目的是调查用含CpG的TLR9-配体1668-硫代硫酸盐（CpG）进行的后处理是否可以调节再灌注鼠MI的炎症和重塑。方法：三十分钟。在12周龄的C57BL / 6小鼠中进行LAD闭塞。ip CpG ip处理小鼠5分钟。再灌注之前。对照组接受PBS。假手术组未发生缺血。M模式超声心动图（3,7和28天）和米勒^®左心室（LV）导管中，其中切出，并收集用于免疫组织化学（6，24个小时，3，7，28天）的心之前执行（7和28天） ，基因表达（6，24个小时，3天;的Taqman ^®RT-qPCR），蛋白质和FACS分析（24小时3天）。结果：CpG处理的小鼠在再灌注7天和28天后显示出明显更好的LV功能。CpG处理后可明显诱导促炎和抗炎细胞因子的蛋白质和mRNA表达。组织学显示，在24小时后，CpG小鼠的巨噬细胞较少，通过FACS分析证实，经典的M1和其他M2a单核细胞均减少。CpG处理可减少细胞凋亡和心肌细胞丢失，并与诱导适应机制有关，例如血红素氧合酶-1和b- / a-MHC比率。CpG-小鼠废除了促纤维化标志物col-Ia和-III诱导，伴随着成纤维细胞减少。这导致形成较小的疤痕。MMP / TIMP差异表达导致CpG的重塑减弱，导致以TLR1和-9依赖性方式保留心脏功能。结论：我们的研究表明CpG后处理的心脏保护机制涉及TLR驱动的炎症调节。接下来是减弱的重塑和保留的LV功能。