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      Heightened efficacy of nitric oxide-based therapies in type II diabetes mellitus and metabolic syndrome

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          Abstract

          Type II diabetes mellitus (DM) and metabolic syndrome are associated with accelerated restenosis following vascular interventions due to neointimal hyperplasia. The efficacy of nitric oxide (NO)-based therapies is unknown in these environments. Therefore, the aim of this study is to examine the efficacy of NO in preventing neointimal hyperplasia in animal models of type II DM and metabolic syndrome and examine possible mechanisms for differences in outcomes. Aortic vascular smooth muscle cells (VSMC) were harvested from rodent models of type II DM (Zucker diabetic fatty), metabolic syndrome (obese Zucker), and their genetic control (lean Zucker). Interestingly, NO inhibited proliferation and induced G 0/G 1 cell cycle arrest to the greatest extent in VSMC from rodent models of metabolic syndrome and type II DM compared with controls. This heightened efficacy was associated with increased expression of cyclin-dependent kinase inhibitor p21, but not p27. Using the rat carotid artery injury model to assess the efficacy of NO in vivo, we found that the NO donor PROLI/NO inhibited neointimal hyperplasia to the greatest extent in type II DM rodents, followed by metabolic syndrome, then controls. Increased neointimal hyperplasia correlated with increased reactive oxygen species (ROS) production, as demonstrated by dihydroethidium staining, and NO inhibited this increase most in metabolic syndrome and DM. In conclusion, NO was surprisingly a more effective inhibitor of neointimal hyperplasia following arterial injury in type II DM and metabolic syndrome vs. control. This heightened efficacy may be secondary to greater inhibition of VSMC proliferation through cell cycle arrest and regulation of ROS expression, in addition to other possible unidentified mechanisms that deserve further exploration.

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          Most cited references 51

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            Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: Part I.

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                Author and article information

                Journal
                American Journal of Physiology-Heart and Circulatory Physiology
                American Journal of Physiology-Heart and Circulatory Physiology
                American Physiological Society
                0363-6135
                1522-1539
                December 2008
                December 2008
                : 295
                : 6
                : H2388-H2398
                Article
                10.1152/ajpheart.00185.2008
                2614532
                18931034
                cb9617cb-4985-4c62-a7a4-a7c0f2bc2f1a
                © 2008

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