MicroRNA-181b Controls Atherosclerosis and Aneurysms Through Regulation of TIMP-3 and Elastin

Karina Di Gregoli*, Nur Najmi Mohamad Anuar, Rosaria Bianco, Stephen J White, Andrew C Newby, Sarah J George, Jason L Johnson

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

46 Citations (Scopus)
245 Downloads (Pure)

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 languageEnglish
Pages (from-to)49-65
Number of pages40
JournalCirculation Research
Volume120
Issue number1
Early online date18 Oct 2016
DOIs
Publication statusPublished - 6 Jan 2017

Keywords

  • Abdominal aortic aneurysm
  • atherosclerosis
  • TIMPs
  • microRNA
  • elastin lamina disruption aneurysm
  • macrophages

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