%0 Journal Article
%T Mechanisms and efficacy of metformin-mediated suppression of established experimental abdominal aortic aneurysms.
%A Xu B
%A Li G
%A Li Y
%A Deng H
%A Cabot A
%A Guo J
%A Samura M
%A Zheng X
%A Chen T
%A Zhao S
%A Fujimura N
%A Dalman RL
%J JVS Vasc Sci
%V 4
%N 0
%D 2023
%M 37168662
暂无%R 10.1016/j.jvssci.2023.100102
%X UNASSIGNED: Metformin treatment attenuates experimental abdominal aortic aneurysm (AAA) formation, as well as reduces clinical AAA diameter enlargement in patients with diabetes. The mechanisms of metformin-mediated aneurysm suppression, and its efficacy in suppressing established experimental aneurysms, remain uncertain.
UNASSIGNED: Experimental AAAs were created in male C57BL/6J mice via intra-aortic infusion of porcine pancreatic elastase. Metformin alone (250 mg/kg), or metformin combined with the 5' AMP-activated protein kinase (AMPK) antagonist Compound C (10 mg/kg), were administered to respective mouse cohorts daily beginning 4 days following AAA induction. Further AAA cohorts received either the AMPK agonist AICA riboside (500 mg/kg) as positive, or vehicle (saline) as negative, controls. AAA progression in all groups was assessed via serial in vivo ultrasonography and histopathology at sacrifice. Cytokine-producing T cells and myeloid cellularity were determined by flow cytometric analyses.
UNASSIGNED: Metformin limited established experimental AAA progression at 3 (-85%) and 10 (-68%) days following treatment initiation compared with saline control. Concurrent Compound C treatment reduced this effect by approximately 50%. In metformin-treated mice, reduced AAA progression was associated with relative elastin preservation, smooth muscle cell preservation, and reduced mural leukocyte infiltration and neoangiogenesis compared with vehicle control group. Metformin also resulted in reduced interferon-γ-, but not interleukin-10 or -17, producing splenic T cells in aneurysmal mice. Additionally, metformin therapy increased circulating and splenic inflammatory monocytes (CD11b+Ly-6Chigh), but not neutrophils (CD11b+Ly-6G+), with no effect on respective bone marrow cell populations.
UNASSIGNED: Metformin treatment suppresses existing experimental AAA progression in part via AMPK agonist activity, limiting interferon-γ-producing T cell differentiation while enhancing circulating and splenic inflammatory monocyte retention.