Inhibition of angiotensin-induced aortic aneurysm by metformin in apolipoprotein E-deficient mice.

ABSTRACT

OBJECTIVE: Metformin is associated with a reduced incidence and growth of abdominal aortic aneurysms (AAAs). The aim of the present study was to investigate the inhibitory effects of metformin on AAA development and possible underlying mechanisms in experimentally induced AAAs in mice, along with the possible synergistic effects of metformin and imatinib. METHODS: Angiotensin II was used to induce AAAs in apolipoprotein E knockout (ApoE -/- ) mice for 28 days. The mice were treated with metformin (n = 11), metformin combined with imatinib (n = 7), or vehicle (n = 12), starting 3 days before angiotensin II infusion. Ultrasound examination was used to analyze aneurysm formation. Cholesterol and blood pressure levels were measured at the start and end of the study. Gene array and quantitative polymerase chain reaction were used to analyze the changes in gene expression in the aorta. Wire myography was used to study vascular function. RESULTS: Metformin (n = 11) suppressed the formation and progression of AAAs by 50% compared with the vehicle controls (n = 12), with no further effects from imatinib (n = 7). Metformin reduced total cholesterol and mRNA expression of SPP1 (encoding osteopontin), MMP12, and the glycoprotein genes Gpnmb and Clec7a. Furthermore, metformin inhibited blood pressure increases and reduced vascular contractions, as determined by wire myography, and restored the anticontractile function of perivascular adipose tissue. CONCLUSION: Metformin inhibited aneurysm formation and progression and normalized vascular function in ApoE -/- mice with no additional effect of imatinib. This might be mediated by the protective effects on vascular endothelial function and perivascular adipose tissue via reduced expression of genes promoting inflammation, including SPP1, MMP12, Gpnmb, and Clec7a. CLINICAL RELEVANCE Retrospective studies of the effects of metformin in patients with aneurysm have so far only been performed of those with type 2 diabetes. The present study shows that metformin has effects on nondiabetic mice and revealed the mechanistic effects mediated by the drug that could also be important to study as outcomes in humans. Future clinical trials using metformin are warranted in patients without diabetes with abdominal aortic aneurysms.