Inhibition Of Microrna-494 Halts Atherosclerotic Plaque Progression And Stabilizes Advanced Atherosclerotic Lesions

Investigating the in vivo effects of miR-494 inhibition on progression and stability of advanced atherosclerotic lesions. LDLr-/- mice were fed a Western Type Diet (WTD) for 10 weeks to induce atherosclerosis. Semi-constrictive collars were placed around both carotid arteries 4 weeks after start of WTD and 6 weeks after collar placement, a subset of mice (N=10) was sacrificed to analyze baseline plaque size and composition. For the remaining mice, WTD was replaced by normal chow and 3rd Generation Antisense (3GA) against miR-494 (3GA-494; N=10) or negative control (3GA-ctrl; N=10) were administered (i.v., 1 mg/mouse) immediately after and at 2 and 4 weeks after diet switch. Mice were sacrificed one week after final injection. 3GA-ctrl mice showed increased carotid artery plaque size compared to baseline, indicating continued atherogenesis, even after lowering plasma cholesterol levels by diet-replacement (before: 863±115 mg/dL vs. after: 214±13 mg/dL). 3GA-494 mice however, showed a significant decrease in carotid artery plaque size compared to control; in fact, 3GA-494 mice had similar plaque sizes to baseline mice (baseline: 30±8*103 µm2, 3GA-ctrl: 56±16*103 µm2 vs. 3GA-494: 23±9*103 µm2, P These results show that treatment with 3GA-494 halts plaque progression in the carotid artery and increases plaque stability in aortic root plaques. Furthermore, 3GA-494 treatment reduces the platelet count, as well as plasma cholesterol levels, which is an additional improvement of cardiovascular risk factors.