Anti-Inflammatory and Antiatherogenic Effects of the NLRP3 Inflammasome Inhibitor Arglabin in ApoE2.Ki Mice Fed a High-Fat Diet. Issue 12 (24th March 2015)

• Record Type: Journal Article
• Authors: Abderrazak, Amna; Couchie, Dominique; Mahmood, Dler Faieeq Darweesh; Elhage, Rima; Vindis, Cécile; Laffargue, Muriel; Matéo, Véronique; Büchele, Berthold; Ayala, Monica Rubio; El Gaafary, Menna; Syrovets, Tatiana; Slimane, Mohamed-Naceur; Friguet, Bertrand; Fulop, Tamas; Simmet, Thomas; El Hadri, Khadija; Rouis, Mustapha
• Is Part Of: Circulation. Volume 131:Issue 12(2015)
• Publication Date: 2015-03-24
• Subjects: arglabin-dimethylaminohydrochloride -- atherosclerosis -- cytokines -- inflammasomes -- inflammation; Blood -- Circulation -- Periodicals; Cardiovascular system -- Periodicals; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; 616.1
• DOI: 10.1161/CIRCULATIONAHA.114.013730
• Languages: English
• ISSNs: 0009-7322

Abstract

Abstract : Background—: This study was designed to evaluate the effect of arglabin on the NLRP3 inflammasome inhibition and atherosclerotic lesion in ApoE2 Ki mice fed a high-fat Western-type diet. Methods and Results—: Arglabin was purified, and its chemical identity was confirmed by mass spectrometry. It inhibited, in a concentration-dependent manner, interleukin (IL)-1β and IL-18, but not IL-6 and IL-12, production in lipopolysaccharide and cholesterol crystal–activated cultured mouse peritoneal macrophages, with a maximum effect at ≈50 nmol/L and EC50 values for both cytokines of ≈ 10 nmol/L. Lipopolysaccharide and cholesterol crystals did not induce IL-1β and IL-18 production in Nlrp3 −/− macrophages. In addition, arglabin activated autophagy as evidenced by the increase in LC3-II protein. Intraperitoneal injection of arglabin (2.5 ng/g body weight twice daily for 13 weeks) into female ApoE2 .Ki mice fed a high-fat diet resulted in a decreased IL-1β plasma level compared with vehicle-treated mice (5.2±1.0 versus 11.7±1.1 pg/mL). Surprisingly, arglabin also reduced plasma levels of total cholesterol and triglycerides to 41% and 42%, respectively. Moreover, arglabin oriented the proinflammatory M1 macrophages into the anti-inflammatory M2 phenotype in spleen and arterial lesions. Finally, arglabin treatment markedly reduced the median lesion areas in the sinus and whole aorta to 54% ( P =0.02) and 41% ( P =0.02), respectively. Conclusions—: Arglabin reduces inflammation and plasma lipids, increases autophagy, and orients tissue macrophages into an anti-inflammatory phenotype in ApoE2 .Ki mice fed a high-fat diet. Consequently, a marked reduction in atherosclerotic lesions was observed. Thus, arglabin may represent a promising new drug to treat inflammation and atherosclerosis. Abstract : Supplemental Digital Content is available in the text.