A 38-specific inhibitor, FR167653, reduces carotid intimal thickening and ameliorates insulin resistance in balloon-injured diabetic rats

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We have reported that p38 MAP kinase activation can alter a process occurring early in atherosclerosis or the glucose metabolism in diabetes. To explore this possibility, we investigated the effects of FR167653, one of the p38-specific inhibitors, on balloon-injured carotid arterial intimal thickening and glucose metabolism by using male Wistar fatty rats (fa / fa), a genetically established obese-hyperglycemic animal model for Type-II diabetes mellitus, and their littermates (Wistar lean rats, Fa / ?).FR167653 at 30 mg・kg-1・day-1 was orally administered to 12-week-old rats for 21 days, and age-matched rats without the agent were used as the respective controls. Balloon catheterization in the left common carotid artery and the thoracic aorta was performed at day 7, and the artery was removed at day 14 for histological analysis and/or the following immunoblot analysis. Compared with the area ratios of the neointima / media of fatty rats without treatment, those of fatty rats with FR1676 … More 53 and lean rats without treatment were significantly decreased to approximately 45%, while those of lean rats with FR167653 to 30%. The administration of FR167653 also decreased the levels of plasma glucose and systolic blood pressure in fatty rats. Treatment with FR167653 suppressed the levels of phosphorylated extracellular signal-regulated protein kinase 1 / 2, p38 and c-jun NH_2-terminal protein kinase, and even the levels of proliferative cell nuclear antigen (PCNA) in balloon-injured thoracic aortae.In an intragastric glucose load, the levels of both glucose and insulin were significantly decreased when fatty rats were treated with 30 mg・kg^<-1>・day^<-1> of FR167653. In cultured vascular smoot muscle cells (VSMCs) from both fatty and lean rats, insulin-stimulated 2-deoxy-D-glucose uptake were dose-dependently activated by FR167653.In this study, we have established that FR167653 has pleiotropic effects on not only the inhibition of intimal thickening in balloon-injured arteries by attenuating the amount of VSMCs but also the amelioration of insulin resistance. In addition, the suppression of intimal thickening by the agent was more remarkable in diabetic rats. These results provide a new insight into the potential cellular mechanisms in the vasculature whereby the suppression of p38 activity by FR167653 may have clinical benefits and contribute to the prevention of atherosclerosis, such as metabolic syndrome. Less