1. CpG postconditioning after reperfused myocardial infarction is associated with modulated inflammation, less apoptosis, and better left ventricular function.
- Author
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Duerr GD, Wu S, Schneider ML, Marggraf V, Weisheit CK, Velten M, Verfuerth L, Frede S, Boehm O, Treede H, Dewald O, Baumgarten G, and Kim SC
- Subjects
- Animals, Anti-Inflammatory Agents administration & dosage, Anti-Inflammatory Agents pharmacology, Anti-Inflammatory Agents therapeutic use, Cells, Cultured, Collagen genetics, Collagen metabolism, Cytokines genetics, Cytokines metabolism, Female, Heme Oxygenase-1 genetics, Heme Oxygenase-1 metabolism, Injections, Intraperitoneal, Macrophages drug effects, Macrophages metabolism, Male, Mice, Mice, Inbred C57BL, Myocardial Infarction drug therapy, Myocardial Reperfusion Injury drug therapy, Myocardium metabolism, Myosin Heavy Chains genetics, Myosin Heavy Chains metabolism, Oligodeoxyribonucleotides administration & dosage, Oligodeoxyribonucleotides pharmacology, Oligodeoxyribonucleotides therapeutic use, Tissue Inhibitor of Metalloproteinases genetics, Tissue Inhibitor of Metalloproteinases metabolism, Toll-Like Receptor 9 agonists, Apoptosis, Ischemic Postconditioning methods, Myocardial Infarction therapy, Myocardial Reperfusion Injury therapy, Ventricular Function, Left
- Abstract
Postconditioning attenuates inflammation and fibrosis in myocardial infarction (MI). The aim of this study was to investigate whether postconditioning with the cytosine-phosphate-guanine (CpG)-containing Toll-like receptor-9 (TLR9) ligand 1668-thioate (CpG) can modulate inflammation and remodeling in reperfused murine MI. Thirty minutes of left descending coronary artery (LAD) occlusion was conducted in 12-wk-old C57BL/6 mice. Mice were treated with CpG intraperitoneally 5 min before reperfusion. The control group received PBS; the sham group did not undergo ischemia. M-mode echocardiography (3, 7, and 28 days) and Millar left ventricular (LV) catheterization were performed (7 and 28 days) before the hearts were excised and harvested for immunohistochemical (6 h, 24 h, 3 days, 7 days, and 28 days), gene expression (6 h, 24 h, and 3 days; Taqman RT-qPCR), protein, and FACS analysis (24 h and 3 days). Mice treated with CpG showed significantly better LV function after 7 and 28 days of reperfusion. Protein and mRNA expressions of proinflammatory and anti-inflammatory cytokines were significantly induced after CpG treatment. Histology revealed fewer macrophages in CpG mice after 24 h, confirmed by FACS analysis with a 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 β-/α-myosin heavy chain (MHC) ratio. Profibrotic markers collagen type Iα (Col-Ια) and Col-III induction was abrogated in CpG mice, accompanied by fewer myofibroblasts. This led to the formation of a smaller scar. Differential matrix metalloproteinase (MMP)/tissue inhibitor of metalloproteinase (TIMP) expression contributed to attenuated remodeling in CpG, resulting in preserved cardiac function in a Toll-like receptor 1- and TLR9-dependent manner. Our study suggests a cardioprotective mechanism of CpG postconditioning, involving Toll-like receptor-driven modulation of inflammation. This is followed by attenuated remodeling and preserved LV function. NEW & NOTEWORTHY Cytosine-phosphate-guanine (CpG) postconditioning seems to mediate inflammation via Toll-like receptor-1 and Toll-like receptor-9 signaling. Enhanced cytokine and chemokine expressions are partly attenuated by IL-10 and matrix metalloproteinase-8 (MMP8) induction, being associated with lower macrophage infiltration and M1-monocyte differentiation. Furthermore, switch from α- to β-MHC and balanced MMP/TIMP expression led to lesser cardiomyocyte apoptosis, smaller scar size, and preserved cardiac function. Data of pharmacological postconditioning have been widely disappointing to date. Our study suggests a new pathway promoting myocardial postconditioning via Toll-like receptor activation.
- Published
- 2020
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