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Heightened efficacy of nitric oxide-based therapies in type II diabetes mellitus and metabolic syndrome.
Heightened efficacy of nitric oxide-based therapies in type II diabetes mellitus and metabolic syndrome.
- Source :
-
American journal of physiology. Heart and circulatory physiology [Am J Physiol Heart Circ Physiol] 2008 Dec; Vol. 295 (6), pp. H2388-98. Date of Electronic Publication: 2008 Oct 17. - Publication Year :
- 2008
-
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 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.
- Subjects :
- Animals
Aorta, Abdominal drug effects
Aorta, Abdominal metabolism
Apoptosis drug effects
Carotid Artery Injuries metabolism
Carotid Artery Injuries pathology
Cell Cycle drug effects
Cell Proliferation drug effects
Cells, Cultured
DNA Replication drug effects
Diabetes Mellitus, Type 2 metabolism
Diabetes Mellitus, Type 2 pathology
Disease Models, Animal
Dose-Response Relationship, Drug
Hyperplasia
Male
Metabolic Syndrome metabolism
Metabolic Syndrome pathology
Muscle, Smooth, Vascular metabolism
Muscle, Smooth, Vascular pathology
Myocytes, Smooth Muscle metabolism
Myocytes, Smooth Muscle pathology
Proline analogs & derivatives
Proline pharmacology
Rats
Rats, Zucker
Reactive Oxygen Species metabolism
S-Nitroso-N-Acetylpenicillamine pharmacology
Triazenes pharmacology
Tyrosine analogs & derivatives
Tyrosine metabolism
Carotid Artery Injuries drug therapy
Diabetes Mellitus, Type 2 drug therapy
Metabolic Syndrome drug therapy
Muscle, Smooth, Vascular drug effects
Myocytes, Smooth Muscle drug effects
Nitric Oxide metabolism
Nitric Oxide Donors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0363-6135
- Volume :
- 295
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Heart and circulatory physiology
- Publication Type :
- Academic Journal
- Accession number :
- 18931034
- Full Text :
- https://doi.org/10.1152/ajpheart.00185.2008