Kathrin Feldmann1, Maria Grandoch1, Christina Kohlmorgen1, Birte Valentin1, Stephen Gerfer1, Nadine Nagy1, Sonja Hartwig2, Stefan Lehr2, Anke C Fender3, Jens W Fischer4. 1. Institute for Pharmacology and Clinical Pharmacology, Medical Faculty, University Hospital, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany; Cardiovascular Research Institute Duesseldorf (CARID), University Hospital, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany. 2. Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center at the Heinrich-Heine-University Duesseldorf, Leibniz Center for Diabetes Research, Duesseldorf, Germany; German Center for Diabetes Research (DZD), 85764, München-Neuherberg, Germany. 3. Institute of Pharmacology, West German Heart and Vascular Center, University Hospital, Essen, Germany. 4. Institute for Pharmacology and Clinical Pharmacology, Medical Faculty, University Hospital, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany; Cardiovascular Research Institute Duesseldorf (CARID), University Hospital, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany. Electronic address: jens.fischer@uni-duesseldorf.de.
Abstract
BACKGROUND AND AIMS: The non-vitamin K oral anticoagulant dabigatran etexilate (dabigatran) is increasingly prescribed to patients with non-valvular atrial fibrillation and venous thromboembolism. Adipose tissue (AT) inflammation during obesity plays a crucial role in the development of insulin resistance, type II diabetes and atherogenesis. The aim of the present study was to investigate the effects of thrombin inhibition by dabigatran in a combined model of diet-induced obesity and atherosclerosis. METHODS: Female Low density lipoprotein receptor knockout (Lldr-/-) mice were fed a high-fat diet containing 5 mg/g dabigatran or matching control for 20 weeks. RESULTS: Dabigatran-treated animals showed increased adipocyte hypertrophy, but reduced numbers of pro-inflammatory M1-polarized macrophages in the adipose tissue. Abundance of pro-inflammatory M1 macrophages was also decreased in the aortic wall of dabigatran-fed mice. Multiple circulating cytokines were reduced, indicating an effect in systemically relevant secretory compartments such as the AT. CONCLUSIONS: Dabigatran treatment reduces pro-inflammatory M1 macrophages in atherosclerotic lesions, thereby contributing to plaque stabilizing and atheroprotective effects of the thrombin inhibitor. This finding is not restricted to the vascular wall but is also present in AT where dabigatran treatment reduced the release of pro-inflammatory cytokines and accumulation of M1 macrophages.
BACKGROUND AND AIMS: The non-vitamin K oral anticoagulant dabigatran etexilate (dabigatran) is increasingly prescribed to patients with non-valvular atrial fibrillation and venous thromboembolism. Adipose tissue (AT) inflammation during obesity plays a crucial role in the development of insulin resistance, type II diabetes and atherogenesis. The aim of the present study was to investigate the effects of thrombin inhibition by dabigatran in a combined model of diet-induced obesity and atherosclerosis. METHODS: Female Low density lipoprotein receptor knockout (Lldr-/-) mice were fed a high-fat diet containing 5 mg/g dabigatran or matching control for 20 weeks. RESULTS:Dabigatran-treated animals showed increased adipocyte hypertrophy, but reduced numbers of pro-inflammatory M1-polarized macrophages in the adipose tissue. Abundance of pro-inflammatory M1 macrophages was also decreased in the aortic wall of dabigatran-fed mice. Multiple circulating cytokines were reduced, indicating an effect in systemically relevant secretory compartments such as the AT. CONCLUSIONS:Dabigatran treatment reduces pro-inflammatory M1 macrophages in atherosclerotic lesions, thereby contributing to plaque stabilizing and atheroprotective effects of the thrombin inhibitor. This finding is not restricted to the vascular wall but is also present in AT where dabigatran treatment reduced the release of pro-inflammatory cytokines and accumulation of M1 macrophages.
Authors: Ibrahim AlZaim; Aya Al-Saidi; Safaa H Hammoud; Nadine Darwiche; Yusra Al-Dhaheri; Ali H Eid; Ahmed F El-Yazbi Journal: Cancers (Basel) Date: 2022-03-25 Impact factor: 6.639