Investigation of the effects of propolis on the development of atherosclerosis in ApoE knockout mice fed on atherogenic diet: Relationship between ADAM protease inhibition and atherosclerosis

ADAM10 and ADAM17, members of the ADAM (a disintengrin and metalloprotease) enzyme family, are known to play an important role in atherosclerosis, a chronic inflammatory process. Propolis, one of the most consumed natural products, is known to have anti-inflammatory activity thanks to the many flavanoids and polyphenols in its structure. However, the effect of propolis on the activity of two enzymes that have a direct effect on the inflammatory process such as ADAM10/17 is not known. We aimed this study to investigate both the inhibition of these enzymes and the effect of inhibition on the atherosclerosis process by creating an experimental atherosclerosis model. In our study, C57BL-6J mice (n=16) were used in the control (C) and sham (S) groups, while ApoE-/- mice (n=48) were used in the case (C), water extract of propolis (WEP), ethanolic extract of propolis (EEP), GW280264X (GW-Synthetic inhibitor) and solvents (DMSO and ethanol) groups. Group K was fed with control diet and all other groups were fed with high cholesterol diet for sixteen weeks. WEP (400mg/kg/day), EEP (200mg/kg/day) and GW (100µg/kg/day) were administered intraperitoneally for the last four weeks. Animals were sacrificed and blood, liver, aorta, heart tissues were collected. In serum, total cholesterol (TC) and triglycerides (TG) were measured by enzymatic colorimetric method, while interleukin-1β (IL-1β), paraoxanase-1 (PON-1) and lipoprotein-associated phospholipase A2 (Lp-PLA2) were measured by ELISA. In aorta, tumor necrosis factor-α (TNF-α), interferon-γ (IFN- γ), myeloperoxidase (MPO), interleukin-6 (IL-6), interleukin-10 (IL-10) and interleukin-12 (IL-12) levels while measured by ELISA, ADAM10/17 activities were measured fluorometrically. Aortic root, liver and heart tissues were examined histopathologically and immunohistochemically (ADAM10 and Sortilin). In the WEP, EEP and GW groups compared to C group; TC, TG, TNF-α, IL-1β, IL-6, IL-12, PLA2, MPO, ADAM10/17 activities, plaque burden, lipid accumulation, ADAM10 and Sortilin levels decreased, while IL-10 and PON-1 levels increased (p<0.003). In our study, it was concluded that propolis decreased inflammation and dyslipidemia in atherosclerosis via ADAM10/17 inhibition.