Anna Zampetaki1, Rizwan Attia2, Ursula Mayr2, Renata S M Gomes2, Alkystis Phinikaridou2, Xiaoke Yin2, Sarah R Langley2, Peter Willeit2, Ruifang Lu2, Bruce Fanshawe2, Marika Fava2, Javier Barallobre-Barreiro2, Chris Molenaar2, Po-Wah So2, Abeera Abbas2, Marjan Jahangiri2, Matthew Waltham2, Rene Botnar2, Alberto Smith2, Manuel Mayr1. 1. 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.). anna.zampetaki@kcl.ac.uk manuel.mayr@kcl.ac.uk. 2. 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.).
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.
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.
Authors: Stefano Tarantini; Cory B Giles; Jonathan D Wren; Nicole M Ashpole; M Noa Valcarcel-Ares; Jeanne Y Wei; William E Sonntag; Zoltan Ungvari; Anna Csiszar Journal: Age (Dordr) Date: 2016-08-26