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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...
Show moreInvestigating 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<0.05). Relative intra-plaque collagen content and macrophage infiltration remained unaltered after treatment. In the aortic root, we did not observe differences in plaque size between the 3GA-treated groups, however, plaque stability was significantly increased upon 3GA-494 treatment. Intra-plaque collagen content was increased in 3GA-494 mice (3GA-ctrl: 37±3% vs. 3GA-494: 52±4%, P<0.05), whereas necrotic core size remained similar (3GA-ctrl: 20±2 vs. %3GA-494: 16±3%). Blood analysis revealed a significant decrease in platelet count in the 3GA-494 group (3GA-ctrl: 1097±109*109 /L vs. 3GA-494: 288±64*109 /L, P<0.05), as well as a further reduction in plasma cholesterol (3GA-ctrl: 214±13 mg/dL vs. 3GA-494: 154±6 mg/dL, P<0.05).
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.
Show less- All authors
- Ingen, E. van; Foks, A.C.; Kröner, M.J.; Agrawal, S.; Kuiper, J.; Quax, P.H.A.; Bot, I.; Nossent, A.Y.
- Date
- 2018-04-30
- Volume
- 114
- Issue
- suppl_1
- Pages
- S57 - S57