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En Face Detection of Nitric Oxide and Superoxide in Endothelial Layer of Intact Arteries
Published on: February 25, 2016
Antioxidative treatment reverses imbalances of nitric oxide synthase isoform expression and attenuates tissue-cGMP
Jörg Bojunga1, Birgit Dresar-Mayert, Klaus-Henning Usadel
1Innere Medizin II, Medizinische Klinik und Poliklinik, Saarland University, Homburg/Saar, Germany. dr_bojunga@web.de
Abstract:
Oxidative stress and impaired bioactivity of vascular nitric oxide (NO) play an important role in the pathogenesis of macro- as well as microangiopathic complications in diabetes mellitus. To determine the cause of this impaired bioactivity, we tested the effect of long-term hyperglycemia and antioxidative treatment on tissue-specific endothelial (e)NOS- and inducible (i)NOS-expression and the main target of NO action, cGMP, in diabetic rats. After 4 weeks of hyperglycemia, eNOS-mRNA expression was significantly down-regulated in all tissues tested. In contrast, iNOS-mRNA was significantly up-regulated and tissue generation of cGMP significantly increased. Treatment with alpha-lipoicacid reversed changes of NOS-isoform expression as well as cGMP-concentration without changing blood glucose levels. In addition, oxidative stress significantly decreased in diabetic rats treated with alpha-lipoicacid. Together, diabetes regulates NOS-isoforms differentially by down-regulating eNOS and up-regulating iNOS. In addition, our data suggest that the cause of impaired endothelial vasodilatation in experimental diabetes is not degradation or inactivation of NO. On the contrary, these results support the concept of decreased reactivity of the vascular smooth muscle to NO or increased NO activity as a possible vascular damaging agent, e.g., by inducing apoptosis in vascular cells. Furthermore, our data show that antioxidative treatment is capable of reversing changes in the NO-cGMP system and may therefore be an important therapeutic option for preventing vascular damage in diabetes mellitus.
Insights
Diabetes alters nitric oxide (NO) pathways, decreasing endothelial NOS and increasing inducible NOS. Antioxidative treatment with alpha-lipoic acid reverses these changes, suggesting a therapeutic role in preventing diabetic vascular complications.
Area of Science:
- Cardiovascular Research
- Endocrinology
- Pharmacology
Background:
- Oxidative stress and impaired nitric oxide (NO) bioactivity contribute to diabetic vascular complications.
- Understanding the specific mechanisms of NO dysregulation in diabetes is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the effects of long-term hyperglycemia and antioxidative treatment on nitric oxide synthase (NOS) isoforms and cyclic guanosine monophosphate (cGMP) in diabetic rats.
- To elucidate the cause of impaired vascular NO bioactivity in experimental diabetes.
Main Methods:
- Assessed tissue-specific endothelial (e)NOS and inducible (i)NOS mRNA expression in diabetic rats.
- Measured cGMP concentrations and oxidative stress markers.
- Evaluated the impact of alpha-lipoic acid treatment on these parameters.
Main Results:
- Hyperglycemia significantly down-regulated eNOS mRNA and up-regulated iNOS mRNA.
- Tissue cGMP generation increased in diabetic rats.
- Alpha-lipoic acid treatment reversed NOS isoform expression and cGMP levels, and reduced oxidative stress without altering blood glucose.
Conclusions:
- Diabetes differentially regulates NOS isoforms, decreasing eNOS and increasing iNOS expression.
- Impaired vasodilation in diabetes may stem from decreased vascular smooth muscle reactivity to NO or increased NO-induced apoptosis, not NO degradation.
- Antioxidative therapy with alpha-lipoic acid can restore the NO-cGMP system, offering a potential strategy for preventing diabetic vascular damage.
