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This Article Full Text Full Text (PDF) All Versions of this Article: 295/6/H2388    most recent 00185.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Ahanchi, S. S. Articles by Kibbe, M. R. PubMed PubMed Citation Articles by Ahanchi, S. S. Articles by Kibbe, M. R.

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

¹Division of Vascular Surgery and Institute for BioNanotechnology in Medicine, Northwestern University, Chicago, Illinois; ²Basic Research Program, SAIC-Frederick, Inc., Frederick; and ³Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, Maryland

Submitted 21 February 2008 ; accepted in final form 14 October 2008

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 G₀/G₁ 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.

proliferation; neointimal hyperplasia; cell cycle; reactive oxygen species; vascular smooth muscle cells