MicroRNA-181b Controls Atherosclerosis and Aneurysms Through Regulation of TIMP-3 and Elastin
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 a number of cardiovascular diseases; although their contributory role to atherosclerotic plaque and abdominal aortic aneurysm (AAA) stability are poorly understood.
Objective: To investigate whether miR-181b regulates TIMP-3 expression and affects atherosclerosis and aneurysms
Methods and Results: Here, we demonstrate that miR-181b was over-expressed in symptomatic human atherosclerotic plaques and abdominal aortic aneurysms, and correlated with decreased expression of predicted miR-181b targets, TIMP-3 and elastin. Utilising the well characterised 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 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 stabilisation of existing plaques and aneurysms. We determined that miR-181b negatively regulates macrophage TIMP-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 the beneficial effects afforded by miR-181b inhibition are largely TIMP-3 dependent, whilst also revealing an additional protective effect through elevating elastin synthesis.
Conclusions: Our findings suggest that management of miR-181b and its target genes provide therapeutic potential for limiting the progression of atherosclerosis and aneurysms, and protecting them from rupture.
- Received June 14, 2016.
- Revision received October 13, 2016.
- Accepted October 18, 2016.