In diabetes, chronic
hyperglycemia,
dyslipidemia,
inflammation and oxidative stress contribute to the progression of macro/microvascular complications. Recently, benefits of the use of
flavonoids in these conditions have been established. This study investigates, in two different mouse models of diabetes, the vasculoprotective effects of the synthetic
flavonoid hidrosmin on endothelial dysfunction and
atherogenesis. In a
type 2 diabetes model of
leptin-receptor-deficient (db/db) mice, orally administered
hidrosmin (600 mg/kg/day) for 16 weeks markedly improved vascular function in aorta and mesenteric arteries without affecting vascular structural properties, as assessed by wire and pressure myography. In
streptozotocin-induced type 1 diabetic
apolipoprotein E-deficient mice,
hidrosmin treatment for 7 weeks reduced
atherosclerotic plaque size and
lipid content; increased markers of plaque stability; and decreased markers of
inflammation, senescence and oxidative stress in aorta.
Hidrosmin showed cardiovascular safety, as neither functional nor structural abnormalities were noted in diabetic hearts. Ex vivo,
hidrosmin induced vascular relaxation that was blocked by
nitric oxide synthase (NOS) inhibition. In vitro,
hidrosmin stimulated endothelial NOS activity and NO production and downregulated
hyperglycemia-induced inflammatory and
oxidant genes in vascular smooth muscle cells. Our results highlight
hidrosmin as a potential add-on
therapy in the treatment of macrovascular complications of diabetes.