Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Cardiac & Cardiovascular Systems, Peripheral Vascular Disease, Cardiovascular System & Cardiology, Atherosclerosis, Inflammation, Mitochondrial ROS, Necrosis, NecroX-7, ISCHEMIA-REPERFUSION INJURY, INDOLE DERIVATIVE NECROX-7, CELL-DEATH, OXIDATIVE STRESS, NECROSIS MODULATOR, PROTEIN HMGB1, INFLAMMATION, APOPTOSIS, ACTIVATION, MONOCYTES, Animals, Bone Marrow Cells, Cholesterol, LDL, Collagen, HMGB1 Protein, Lipid Peroxidation, Macrophages, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, ApoE, Organic Chemicals, Oxidative Stress, Plaque, Atherosclerotic, 1102 Cardiorespiratory Medicine and Haematology, 1103 Clinical Sciences, Cardiovascular System & Hematology, 3201 Cardiovascular medicine and haematology, 3202 Clinical sciences

Abstract:

BACKGROUND AND AIMS: A large necrotic core is a key feature of atherosclerotic plaque instability. Necrotic cellular debris accumulates in the lipid-rich core and promotes inflammation, destabilization and ultimately rupture of the plaque. Although the role of necrosis in atherosclerosis is rather clear-cut, not many strategies have been performed up till now to specifically target plaque necrosis. In the present study, we tested the plaque stabilizing potential of NecroX-7, a novel compound with antioxidative and anti-necrotic properties. METHODS: Male apolipoprotein E (Apoe) knockout mice were treated with NecroX-7 (30 mg/kg) or vehicle, 3 times per week, via intraperitoneal injections for 16 weeks. Meanwhile, mice were fed a western-type diet to induce plaque formation. RESULTS: NecroX-7 reduced total plaque burden in the thoracic aorta as compared to vehicle-treated mice, without affecting total plasma cholesterol. Plaques in the aortic root of NecroX-7-treated mice showed a significant decrease in necrotic core area, 8-oxodG, iNOS and MMP13 expression, while collagen content and minimum fibrous cap thickness were increased. Moreover, NecroX-7 treatment reduced the expression of multiple inflammation markers such as TNFα, IL1β, iNOS, HMGB1 and RAGE in a NF-κB-dependent manner. In vitro, NecroX-7 prevented tert-butyl hydroperoxide (tBHP)-induced mitochondrial ROS formation, necrosis, iNOS expression and HMGB1 release in primary macrophages. CONCLUSIONS: NecroX-7 improves features of plaque stability in Apoe knockout mice by reducing necrotic core formation, oxidative stress and inflammation, and by increasing collagen deposition and fibrous cap thickness. Therefore, NecroX-7 could be a promising pleiotropic drug for the treatment of atherosclerosis.