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From the King's British Heart Foundation Centre (A.Z., R.A., U.M., R.S.M.G., A.P., X.Y., S.R.L., R.L., B.F., M.F., J.B.-B., C.M., A.A., M.W., R.B., A.S., M.M.) and Institute of Psychiatry (P.-W.S.), King's College London, United Kingdom; Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom (P.W.); and Department of Cardiac Surgery, St George's Healthcare NHS Trust, London, United Kingdom (M.F., M.J.).
Published: October 2014
AI Article Synopsis
Article Abstract
Rationale: Abdominal aortic aneurysms constitute a degenerative process in the aortic wall. Both the miR-29 and miR-15 families have been implicated in regulating the vascular extracellular matrix.
Objective: Our aim was to assess the effect of the miR-15 family on aortic aneurysm development.
Methods And Results: Among the miR-15 family members, miR-195 was differentially expressed in aortas of apolipoprotein E-deficient mice on angiotensin II infusion. Proteomics analysis of the secretome of murine aortic smooth muscle cells, after miR-195 manipulation, revealed that miR-195 targets a cadre of extracellular matrix proteins, including collagens, proteoglycans, elastin, and proteins associated with elastic microfibrils, albeit miR-29b showed a stronger effect, particularly in regulating collagens. Systemic and local administration of cholesterol-conjugated antagomiRs revealed better inhibition of miR-195 compared with miR-29b in the uninjured aorta. However, in apolipoprotein E-deficient mice receiving angiotensin II, silencing of miR-29b, but not miR-195, led to an attenuation of aortic dilation. Higher aortic elastin expression was accompanied by an increase of matrix metalloproteinases 2 and 9 in mice treated with antagomiR-195. In human plasma, an inverse correlation of miR-195 was observed with the presence of abdominal aortic aneurysms and aortic diameter.
Conclusions: We provide the first evidence that miR-195 may contribute to the pathogenesis of aortic aneurysmal disease. Although inhibition of miR-29b proved more effective in preventing aneurysm formation in a preclinical model, miR-195 represents a potent regulator of the aortic extracellular matrix. Notably, plasma levels of miR-195 were reduced in patients with abdominal aortic aneurysms suggesting that microRNAs might serve as a noninvasive biomarker of abdominal aortic aneurysms.
