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.

Association of IL-10 and CRP with Pulse Wave Velocity in Patients with Abdominal Aortic Aneurysm

“…In the subgroup of males with AAA and T2DM who were treated with metformin, we observed a negative correlation between CRP and PWVcf. This suggests that metformin decreases arterial stiffness in subjects with AAA and is in accordance with results in mice showing that metformin reduces vascular contraction [22].…”

“…Metformin use in AAA patients is strongly associated with a slower AAA growth rate [ 19 , 20 , 21 ]. Kunath et al (2021) demonstrated that metformin reduced vascular contraction and restored the anti-contractile function of perivascular adipose tissue in a mouse model of diabetes [ 22 ]. Metformin was also shown to decrease arterial stiffness in patients with non-alcoholic fatty liver disease [ 23 ] and polycystic ovary syndrome [ 24 ].…”

Metformin suppresses vascular smooth muscle cell senescence by promoting autophagic flux

“…Metformin is a biguanide capable of relieving age-associated pathologies and increasing healthspan and was the first tested product showing aging-targeting effects in a clinical study with a large sample: the TAME (targeting aging by metformin) study [1] . Several studies have demonstrated that metformin could alleviate aging and age-related phenotypes [2] , [3] , [4] by suppressing senescence through mechanisms like redox balance, autophagy, inflammatory cytokines, and endothelial function [5] , [6] , [7] , [8] , [9] .…”

Development of pharmacotherapies for abdominal aortic aneurysms

“…Yang et al reported a significant reduction in IL-6, IL-1β, and TNF-α expression in mouse AAA tissues versus positive controls [ 150 ]. Alternatively, one group observed no significant difference between metformin treated mouse tissue and positive controls when comparing expression of IL-1β, IL-4, IL-16, and INF-γ – in fact, an increase compared to PBS infused negative control mice was seen with metformin administration [ 152 ]. While these two studies both used the AngII infusion + ApoE−/− mouse model of AAA, one used 300 mg/kg/day in drinking water while the latter used 100 mg/kg/day with differing lengths of pretreatment, making comparative analysis difficult [ 150 , 152 ].…”

“…On the other hand, conclusions regarding metformin administration’s effect on MMPs in the AAA wall are not in agreement. Some groups have found a reduction in the activity and mRNA levels of both MMP-2 and MMP-9 while others did not see a significant change [ 10 , 148 , 150 , 152 ]. In fact, one group did not see any increase in MMP-2 expression in the AngII positive controls, something regularly seen in other studies [ 10 ].…”