Abstract
Rationale: Atherosclerosis and aneurysms are leading causes of mortality worldwide. MicroRNAs (miRs) are key determinants of gene and protein expression, and atypical miR expression has been associated with many cardiovascular diseases; although their contributory role to atherosclerotic plaque and abdominal aortic aneurysm stability are poorly understood.
Objective: To investigate whether miR-181b regulates tissue inhibitor of metalloproteinase-3 expression and affects atherosclerosis and aneurysms.
Methods and Results: Here, we demonstrate that miR-181b was overexpressed in symptomatic human atherosclerotic plaques and abdominal aortic aneurysms and correlated with decreased expression of predicted miR-181b targets, tissue inhibitor of metalloproteinase-3, and elastin. Using the well-characterized mouse atherosclerosis models of Apoe−/− and Ldlr−/−, we observed that in vivo administration of locked nucleic acid anti-miR-181b retarded both the development and the progression of atherosclerotic plaques. Systemic delivery of anti-miR-181b in angiotensin II–infused Apoe−/− and Ldlr−/− mice attenuated aneurysm formation and progression within the ascending, thoracic, and abdominal aorta. Moreover, miR-181b inhibition greatly increased elastin and collagen expression, promoting a fibrotic response and subsequent stabilization of existing plaques and aneurysms. We determined that miR-181b negatively regulates macrophage tissue inhibitor of metalloproteinase-3 expression and vascular smooth muscle cell elastin production, both important factors in maintaining atherosclerotic plaque and aneurysm stability. Validation studies in Timp3−/− mice confirmed that the beneficial effects afforded by miR-181b inhibition are largely tissue inhibitor of metalloproteinase-3 dependent, while also revealing an additional protective effect through elevating elastin synthesis.
Conclusions: Our findings suggest that the management of miR-181b and its target genes provides therapeutic potential for limiting the progression of atherosclerosis and aneurysms and protecting them from rupture.
Original language | English |
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Pages (from-to) | 49-65 |
Number of pages | 40 |
Journal | Circulation Research |
Volume | 120 |
Issue number | 1 |
Early online date | 18 Oct 2016 |
DOIs | |
Publication status | Published - 6 Jan 2017 |
Keywords
- Abdominal aortic aneurysm
- atherosclerosis
- TIMPs
- microRNA
- elastin lamina disruption aneurysm
- macrophages
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Professor Sarah J George
- Life Sciences Faculty Office - Dean of the Faculty of Health Sciences
Person: Academic
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Professor Jason L Johnson
- Bristol Medical School (THS) - Professor of Cardiovascular Pathology
Person: Academic