Role of miR-195 in Aortic Aneurysmal Disease
Rationale: Abdominal aortic aneurysms (AAA) 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: 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 upon angiotensin II infusion. Proteomics analysis of the secretome of murine aortic smooth muscle cells, following 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 to 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 aneurysm formation. 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 AAA 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 AAA suggesting that miRNAs might serve as a noninvasive biomarker of AAA.
- Received May 13, 2014.
- Revision received September 6, 2014.
- Accepted September 8, 2014.