The protective effect and underlying mechanism of metformin on neointima formation in fructose-induced insulin resistant rats

Abstract

BackgroundInsulin resistance is strongly associated with the development of type 2 diabetes and cardiovascular disease. However, the underlying mechanisms linking insulin resistance and the development of atherosclerosis have not been fully elucidated. Moreover, the protective effect of antihyperglycemic agent, metformin, is not fully understood. This study investigated the protective effects and underlying mechanisms of metformin in balloon-injury induced stenosis in insulin resistant rats.MethodsAfter 4 weeks high fructose diet, rats received balloon catheter injury on carotid arteries and were sacrificed at 1 and 4 weeks post injury. Biochemical, histological, and molecular changes were investigated.ResultsPlasma levels of glucose, insulin, total cholesterol, triglyceride, free fatty acids, and methylglyoxal were highly increased in fructose-induced insulin resistant rats and treatment with metformin significantly improved this metabolic profile. The neointimal formation of the carotid arteries was enhanced, and treatment with metformin markedly attenuated neointimal hyperplasia. A significant reduction in BrdU-positive cells in the neointima was observed in the metformin-treated group (P < 0.01). Insulin signaling pathways were inhibited in insulin resistant rats while treatment with metformin enhanced the expression of insulin signaling pathways. Increased expression of JNK and NFKB was suppressed following metformin treatment. Vasoreactivity was impaired while treatment with metformin attenuated phenylephrine-induced vasoconstriction and enhanced methacholine-induced vasorelaxation of the balloon injured carotid arteries in insulin resistant rats.ConclusionThe balloon-injury induced neointimal formation of the carotid arteries is enhanced by insulin resistance. Treatment with metformin significantly attenuates neointimal hyperplasia through inhibition of smooth muscle cell proliferation, migration, and inflammation as well as by improvement of the insulin signaling pathway.

Dopamine D4 receptors inhibit proliferation and migration of vascular smooth muscle cells induced by insulin via down-regulation of insulin receptor expression

“…The carotid artery-injured rats were then intraperitoneally injected with PD168077 (6 mg/kg/d) for 14 days to investigate the role of PD168077 in neointimal formation in vivo. Consistent with previous reports [21,23], a significant increase in neointimal formation was found 2 weeks after the balloon injury of the carotid artery (Figure 5A and B). Compared with balloon injury and vehicle-injected group, PD168077 significantly inhibited neointimal formation, associated with a decrease in the intima/media (I/M) ratio (Figure 5C and D).…”

Metformin ameliorates the proinflammatory state in patients with carotid artery atherosclerosis through sirtuin 1 induction

“…Inhibition of proinflammatory factors can further result in the reduction of neointima volume in metformin treatment. 23 However, neither IL-4 protein nor mRNA level was altered by metformin. The main reason might be that Abbreviations: BP, blood pressure; HDL, high-density lipoprotein; hs-CRP, high-sensitivity C-reactive protein; LDL, low-density lipoprotein.…”

Adipose‐derived protein omentin prevents neointimal formation after arterial injury

“…Administration of AICAR or metformin also suppresses neointimal hyperplasia after vascular injury in rats (26)(27)(28). Moreover, AMPKa2 deficiency contributes to enhancement of neointimal hyperplasia after arterial injury (27).…”