Cardiovascular research, 2017-04, Vol.113 (5), p.475-487
2017
Details
- Autor(en) / Beteiligte
- Titel
- Topiramate modulates post-infarction inflammation primarily by targeting monocytes or macrophages
- Ist Teil von
- Cardiovascular research, 2017-04, Vol.113 (5), p.475-487
- Ort / Verlag
- England
- Erscheinungsjahr
- 2017
- Link zum Volltext
- Quelle
- Oxford Journals 2020 Medicine
- Beschreibungen/Notizen
- Monocytes/macrophages response plays a key role in post-infarction inflammation that contributes greatly to post-infarction ventricular remodelling and cardiac rupture. Therapeutic targeting of the GABAA receptor, which is enriched in monocytes/macrophages but not expressed in the myocardium, may be possible after myocardial infarction (MI). After MI was induced by ligation of the coronary artery, C57BL/6 mice were intraperitoneally administered with one specific agonist or antagonist of the GABAA receptor (topiramate or bicuculline), in the setting of presence or depletion of monocytes/macrophages. Our data showed that within the first 2 weeks after MI, when monocytes/macrophages dominated, in contrast with bicuculline, topiramate treatment significantly reduced Ly-6Chigh monocyte numbers by regulating splenic monocytopoiesis and promoted foetal derived macrophages preservation and conversion of M1 to M2 or Ly-6Chigh to Ly-6Clow macrophage phenotype in the infarcted heart, though GABAAergic drugs failed to affect M1/M2 or Ly-6Chigh/Ly-6Clow macrophage polarization directly. Accordingly, pro-inflammatory activities mediated by M1 or Ly-6Chigh macrophages were decreased and reparative processes mediated by M2 or Ly-6Clow macrophages were augmented. As a result, post-infarction ventricular remodelling was attenuated, as reflected by reduced infarct size and increased collagen density within infarcts. Echocardiographic indices, mortality and rupture rates were reduced. After depletion of monocytes/macrophages by clodronate liposomes, GABAAergic drugs exhibited no effect on cardiac dysfunction and surrogate clinical outcomes. Control of the GABAA receptor activity in monocytes/macrophages can potently modulate post-infarction inflammation. Topiramate emerges as a promising drug, which may be feasible to translate for MI therapy in the future.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0008-6363eISSN: 1755-3245DOI: 10.1093/cvr/cvx027Titel-ID: cdi_proquest_miscellaneous_1881268171
- Format
- –
- Schlagworte
- Animals, Anti-Inflammatory Agents - pharmacology, Antigens, Ly - metabolism, Collagen - metabolism, Disease Models, Animal, Fibrosis, Fructose - analogs & derivatives, Fructose - pharmacology, GABA Agonists - pharmacology, Heart Rupture, Post-Infarction - metabolism, Heart Rupture, Post-Infarction - physiopathology, Heart Rupture, Post-Infarction - prevention & control, Heart Ventricles - drug effects, Heart Ventricles - metabolism, Heart Ventricles - pathology, Heart Ventricles - physiopathology, Macrophages - drug effects, Macrophages - metabolism, Mice, Inbred C57BL, Monocytes - drug effects, Monocytes - metabolism, Myocardial Infarction - drug therapy, Myocardial Infarction - metabolism, Myocardial Infarction - pathology, Myocardial Infarction - physiopathology, Myocarditis - metabolism, Myocarditis - pathology, Myocarditis - physiopathology, Myocarditis - prevention & control, Myocardium - metabolism, Myocardium - pathology, Phenotype, Receptors, GABA - drug effects, Receptors, GABA - metabolism, Receptors, GABA-A - drug effects, Receptors, GABA-A - metabolism, Time Factors, Topiramate, Ventricular Dysfunction, Left - metabolism, Ventricular Dysfunction, Left - physiopathology, Ventricular Dysfunction, Left - prevention & control, Ventricular Function, Left - drug effects, Ventricular Remodeling - drug effects