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

Abstract

Inhibition of miR-494 reduces early carotid artery atherosclerosis. However, patients generally present with advanced atherosclerosis. Therefore, we investigated the effect of miR-494 inhibition on advanced atherosclerotic plaques. LDLr-/- mice were placed on a Western Type Diet (WTD). After four weeks, semi-constrictive collars were placed around both carotid arteries to induce local plaque formation. After 10 weeks of WTD, a subset of mice (n 10) was sacrificed as baseline. Remaining mice were placed on normal chow and 3rd Generation Antisense Oli- gonucleotides (3GAs) against miR-494 (3GA-494; n¼10) or negative control (3GA-ctrl; n¼10) were administered (i.v., 1 mg/mouse) imme- diately and at two and four weeks after diet switch. After 5 weeks, all mice were sacrificed. 3GA-ctrl mice showed increased carotid artery plaque size compared to baseline, even though plasma cholesterol levels were reduced upon diet-replacement (before: 863±115 mg/dL vs. after: 214±13 mg/dL). 3GA-494 treatment resulted in a further cholesterol reduction (3GA-494: 154±6 mg/dL, P decreased compared to control and 3GA-494 mice had similar plaque sizes to baseline mice (baseline: 30±8*103 mm2, 3GA-ctrl: 56±16*103 mm2 vs. 3GA-494: 23±9*103 mm2, P plaque size remained similar between groups, however, increased intra-plaque collagen (3GA- ctrl: 37±3% vs. 3GA-494: 55±3%, P 3GA-494: 12±1%, P¼0.1) was reduced after miR-494 inhibition. Our 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 plasma cholesterol els.