Abstract
Acid sphingomyelinase (aSMase) plays an important role in endothelial dysfunction. Here, we show that elevated aSMase activity and ceramide content were reduced by desipramine treatment in diabetic animals. The inhibitor of aSMase, desipramine, improved vascular dysfunction in db/db mice. High glucose (HG)-induced up-regulation of aSMase activity and ceramide levels were restored by treatment with aSMase siRNA or desipramine in endothelial cells. In addition, aSMase siRNA or desipramine treatment increased the release of nitric oxide (NO) and the phosphorylation of endothelial NO synthase (eNOS) in diabetic mouse aortas and aortic endothelial cells with HG.These results indicate that inhibition of aSMase/ceramide pathway improves endothelium-dependent vascular relaxation (EDR) largely through regulating the eNOS/NO pathway in diabetic animals.
Highlights
Diabetes includes a group of chronic diseases characterized by hyperglycemia and/or hyperinsulinemia
Our findings extend our previous research in which we reported that the negative effects of High glucose (HG) on the Akt/endothelial nitric oxide (NO) synthase (eNOS)/NO signaling pathway could be improved by inhibiting ceramide synthesis in vitro [19]
The present study determined that treatment with the acid sphingomyelinase (aSMase) inhibitor, desipramine, prevented ceramide accumulation and ameliorated glycemia control and insulin resistance in diabetic animals
Summary
Diabetes includes a group of chronic diseases characterized by hyperglycemia and/or hyperinsulinemia. Vascular complications are the most serious manifestations of these diseases and the leading cause of death in diabetic patients. The sphingomyelinase pathway is an important regulator of ceramide metabolism in diabetes [7]. Activation of acid sphingomyelinase (aSMase) was observed in diabetic animals and patients [8,9,10]. Previous studies reported that inhibition of ceramide accumulation improved vascular function by regulating endothelial NO synthase (eNOS) activity and NO generation [6,11,12,13]. ASMase/ceramide metabolism could be a potent therapeutic target for diabetic vascular complications. The present study investigated the hypothesis that in vivo and in vitro treatment with aSMase siRNA or desipramine improves vascular function in diabetic animals by inhibiting aSMase activity and ceramide accumulation
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