Effect Of Metformin On Atherosclerosis In Rabbits And Its Molecular Mechanism

Metformin has been an important drug for treatment of type 2diabetes(T2D)for decades.It is the most widely used oral antihyperglycemic agent and reduces macrovascular complications in type 2 diabetic patients.However,the underlying mechanisms of action remain elusive.The present study aimed at investigating the possible effects of metformin on the progression of atherosclerosis in a rabbit model.The rabbit atherosclerosis model was established by an atherogenic diet fed to the rabbits.New Zealand White rabbits were randomly divided into three groups(10/group): the Ctrl group(fed with a chow diet),and two experimental groups,AS group and Met group(both received the atherogenic diet).After a 2-week acclimatization,the rabbits in the AS and Met groups were administered placebo or metformin daily by gavage for 10 weeks,respectively.Metformin administration did not obviously alter plasma lipid metabolism,though the atherogenic diet induced significant increases in these parameters.Compared with the AS group,metformin significantly attenuated the levels of inflammatory factors.Metformin significantly reduced the atherosclerosis burden,and the lesional macrophage content,compared with the AS group.Furthermore,aortic mRNA expression of adhesion molecules and inflammatory cytokines in the Met group was also significantly weakened compared with the AS group.Isolated the monocytes and vascular endothelial cells of rabbits and used them to simulate the adhesion of monocytes to endothelial cells.Metformin treatment reduced monocytes adhesion to ECs and adhesion molecular expression.Our results show that metformin inhibits monocyte adhesion and adhesion molecules expression by blocking NF-kB translocation.We also studied the effect of metformin on macrophage inflammatory factor secretion,we found that metformin can significantly reduce the levels of inflammatory cytokines secreted by macrophages.Our results suggest that metformin retarded the progression of atherosclerosis,possibly by suppressing monocyte adhesion and inflammatory responses.