The Effect Of Metformin On The Pathogenesis Of Abdominal Aortic Aneurysm And Its Molecular Mechanism

Objective:To study the effect of metformin(Met)on abdominal aortic aneurysm(AAA)model of elastase perfusion-inducted rats,to explore possible molecular mechanism of Met in treatment of AAA,and to provide laboratory basis for the clinical application of Met in the control of AAA.Research methods:This study was mainly on animal experiments.In the animal experiment,30 SD rats were randomly divided into 3 groups,10 cases in each group.20rats were perfused with elastase to construct AAA animal model,they were included in AAA group and AAA with Met group.The 10 rats given normal saline perfusion were enrolled as control group.The gastric perfusion with Met[100mg/(kg·d)]was performed in AAA+Met group every day.After molding,feeding lasted for 28d.Then the rats were sacrificed.The maximal diameter of the abdominal aorta was measured.The incidence of AAA of each group was calculated.Some arteries were selected to make paraffin sections.HE staining was performed to observe integrity of aortic wall.The immunohistochemistry was performed to measure expression levels of vascular smooth muscle CD68~+macrophage.Western blot was performed to detect the expression of AMP-activated protein kinase(AMPK),phosphorylation-AMPK(p-AMPK),phosphorylation-mammalian target of rapamycin(p-mTOR),p70 ribosomal S6kinse(p70S6K)and eukarytic initiation factor 4E binging protein 1(4EBP1)in vascular smooth muscle.Results:1)Incidence of AAA:The incidence rates of AAA in control group,AAA group and AAA+Met group were 0%,80%and 30%,respectively.(P<0.05).The incidence of AAA in AAA group was significantly higher than that in control group(P<0.05).AAA+Met group was significantly lower than AAA group(P<0.05).2)Measurement of aortic diameter:There were significant differences in maximum diameter of abdominal aorta among control group,AAA group and AAA+Met group(P<0.05).Compared with control group,maximum diameters of abdominal aorta in AAA group and AAA+Met group were significantly increased(P<0.05).The increasing trend in AAA+Met group was lower than that in AAA group(P<0.05).2)HE staining experiment:Compared with control group,vascular wall of AAA group and AAA+Met group was significantly thickened(P<0.05).There was increase of inflammatory cell infiltration in intima of arterial membrane and outer membrane.The thickening degree of vascular wall and increase of inflammatory cell infiltration in AAA+Met group were less than those in AAA group(P<0.05).3)Immunohistochemistry experiment:There were differences in expression of CD68+macrophage in vascular wall among all groups(P<0.05).The expression of CD68+macrophage in vascular wall of AAA group was significantly higher than that of control group and AAA+Met group(P<0.05).AAA+Met group was significantly lower than AAA group(P<0.05).4)Western blot detection:There was no significant difference in expression of AMPK protein among all groups(P>0.05).Compared with control group,p-AMPK level in AAA group and AAA+Met group was significantly decreased(P<0.05),while p-mTOR,p70S6K and 4EBP1 protein levels were significantly increased(P<0.05).The increase or decrease of each protein expression in AAA+Met group was less than that in AAA group(P<0.05).Conclusion:Met can inhibit increase of abdominal aorta and thickening of vascular wall in elastase-inducted model rates,and inhibit the occurrence of AAA.The mechanism may be related to Met increasing AMPK pathway activity,decreasing p-mTOR and expression of its signaling pathway,thus inhibiting inflammatory cell infiltration and thickening of vascular wall.