Inhibition of neointima hyperplasia by the combined therapy of linagliptin and metformin via AMPK/Nox4 signaling in diabetic rats

Neointima hyperplasia is the pathological basis of atherosclerosis and restenosis which have been associated with diabetes mellitus (DM). It is controversial for linagliptin and metformin to protect against vascular neointimal hyperplasia caused by DM. Given the combined therapy of linagliptin and metformin in clinical practice, we investigated whether the combination therapy inhibited neointimal hyperplasia in the carotid artery in diabetic rats. Neointima hyperplasia in the carotid artery was induced by balloon-injury in the rats fed with high fat diet (HFD) combined with low dose streptozotocin (STZ) administration. In vitro, vascular smooth muscle cells (VSMCs) were incubated with high glucose (HG, 30 mM) and the proliferation, migration, apoptosis and collagen deposition were analyzed in VSMCs. We found that the combined therapy, not the monotherapy of linagliptin and metformin significantly inhibited the neointima hyperplasia and improved the endothelium-independent contraction in the balloon-injured cardia artery of diabetic rats, which was associated with the inhibition of superoxide (O2−.) production in the cardia artery. In vitro, HG-induced VSMC remodeling was shown as the remarkable upregulation of PCNA, collagan1, MMP-9, Bcl-2 and migration rate as well as the decreased apoptosis rate. Such abnormal changes were dramatically reversed by the combined use of linagliptin and metformin. Moreover, the AMP-activated protein kinase (AMPK)/Nox4 signal pathway was found to mediate VSMC remodeling responding to HG. Linagliptin and metformin were synergistical to target AMPK/Nox4 signal pathway in VSMCs incubated with HG and in the cardia artery of diabetic rats, which was superior to the monotherapy. We demonstrated that the potential protection of the combined use of linagliptin and metformin on VSMC remodeling through AMPK/Nox4 signal pathway, resulting in the improvement of neointima hyperplasia in diabetic rats. This study provided new therapeutic strategies for vascular stenosis associated with diabetes. [Display omitted] •Balloon-mediated injury resulted in the neointima hyperplasia in diabetic rats.•Linagliptin and metformin significantly inhibited the neointima hyperplasia.•Linagliptin and metformin improved the endothelium-independent vasocontraction.•Linagliptin and metformin were synergistical to target AMPK/Nox4 in VSMCs.