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

Research output: Contribution to journalArticle

35 Citations (Scopus)

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 pages17
JournalCirculation Research
Volume120
Issue number1
DOIs
Publication statusPublished - 6 Jan 2017
Externally publishedYes

Fingerprint

Tissue Inhibitor of Metalloproteinase-3
Elastin
MicroRNAs
Aneurysm
Atherosclerosis
Atherosclerotic Plaques
Abdominal Aortic Aneurysm
Apolipoproteins E
Validation Studies
Abdominal Aorta
Thoracic Aorta
Vascular Smooth Muscle
Angiotensin II
Smooth Muscle Myocytes
Aorta
Rupture
Cardiovascular Diseases
Collagen
Macrophages
Gene Expression

Keywords

  • aortic aneurysm, abdominal
  • atherosclerosis
  • macrophages
  • microRNAs
  • tissue inhibitor of metalloproteinase-3

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

MicroRNA-181b Controls Atherosclerosis and Aneurysms Through Regulation of TIMP-3 and Elastin. / Di Gregoli, Karina; Mohamad Anuar, Nur Najmi; Bianco, Rosaria; White, Stephen J.; Newby, Andrew C.; George, Sarah J.; Johnson, Jason L.

In: Circulation Research, Vol. 120, No. 1, 06.01.2017, p. 49-65.

Research output: Contribution to journalArticle

Di Gregoli, Karina ; Mohamad Anuar, Nur Najmi ; Bianco, Rosaria ; White, Stephen J. ; Newby, Andrew C. ; George, Sarah J. ; Johnson, Jason L. / MicroRNA-181b Controls Atherosclerosis and Aneurysms Through Regulation of TIMP-3 and Elastin. In: Circulation Research. 2017 ; Vol. 120, No. 1. pp. 49-65.
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T1 - MicroRNA-181b Controls Atherosclerosis and Aneurysms Through Regulation of TIMP-3 and Elastin

AU - Di Gregoli, Karina

AU - Mohamad Anuar, Nur Najmi

AU - Bianco, Rosaria

AU - White, Stephen J.

AU - Newby, Andrew C.

AU - George, Sarah J.

AU - Johnson, Jason L.

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AB - 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.

KW - aortic aneurysm, abdominal

KW - atherosclerosis

KW - macrophages

KW - microRNAs

KW - tissue inhibitor of metalloproteinase-3

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