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Antiatherogenic effects of S-nitroso-N-acetylcysteine in hypercholesterolemic LDL receptor knockout mice
M H Krieger1, K F R Santos, S M Shishido
1Departamento de Fisiologia e Biofísica, Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP), SP, Brazil. kriegerm@unicamp.br
Background:
The pathophysiology of the NO/NO synthase system and dysfunctional changes in the endothelium in the early phases of the atherogenic process are incompletely understood. In this study, we investigated the effects of the nitrosothiol NO donor S-nitroso-N-acetylcysteine (SNAC) in the early prevention of plaque development in the hypercholesterolemic LDLr-/- mice as well as the changes in endothelium-dependent relaxation and NO synthase expression.
Methods And Results:
LDLr-/- mice were fed a 1.25% cholesterol-enriched diet for 15 days. Plasma cholesterol/triglyceride levels increased and this increase was accompanied by the development of aortic root lesions. Aortic vasorelaxation to acetylcholine was increased, although endothelium-independent relaxation in response to sodium nitroprusside did not change, which suggest stimulated NO release enhanced. This dysfunction was associated with enhanced aortic superoxide production and with increased levels of constitutive NOS isoform expression, particularly neuronal NOS. SNAC (S-nitroso-N-acetylcysteine) administration (0.51 micromol/kg/day i.p. for 15 days) decreased the extent of the plaque by 55% in hypercholesterolemic mice, but had no effects on vasomotor changes. It did, however, lead to a decrease in constitutive NOS expression. The SNAC induced only minor changes in plasma lipid profile.
Conclusion:
The present study has shown that, in early stages of plaque development in LDLr-/- mice, specific changes in NO/NO synthase system develop, that are characterized by increased endothelium-dependent vasorelaxation and increased constitutive NOS expression. Since the development of plaque and the indicator of endothelial cell dysfunction were prevented by SNAC, such treatment may constitute a novel strategy for the halting of progression of early plaque.
Insights
The nitrosothiol NO donor S-nitroso-N-acetylcysteine (SNAC) reduced early plaque development in hypercholesterolemic mice by 55%. SNAC treatment also decreased constitutive nitric oxide synthase (NOS) expression, suggesting a novel strategy for preventing early atherosclerosis.
Area of Science:
- Cardiovascular Research
- Endothelial Function
- Nitric Oxide Biology
Background:
- Atherogenesis involves complex endothelial dysfunction and alterations in the nitric oxide (NO)/NO synthase (NOS) system.
- Early pathological changes in the NO/NOS pathway during atherogenesis are not fully understood.
Purpose of the Study:
- To investigate the effects of S-nitroso-N-acetylcysteine (SNAC), an NO donor, on early plaque development in hypercholesterolemic mice.
- To analyze changes in endothelium-dependent relaxation and NOS expression.
Main Methods:
- Administered a cholesterol-enriched diet to LDLr-/- mice for 15 days.
- Assessed aortic root lesions, plasma lipid profiles, and vasorelaxation responses.
- Measured aortic superoxide production and NOS isoform expression.
- Treated mice with SNAC (0.51 micromol/kg/day) for 15 days.
Main Results:
- Cholesterol-enriched diet induced aortic root lesions and increased plasma lipids.
- Endothelium-dependent vasorelaxation to acetylcholine was enhanced, suggesting stimulated NO release.
- Aortic superoxide production and constitutive NOS expression, particularly neuronal NOS, were increased.
- SNAC administration reduced plaque extent by 55% without affecting vasorelaxation or lipid profiles.
- SNAC treatment decreased constitutive NOS expression.
Conclusions:
- Early plaque development in hypercholesterolemic mice is associated with increased endothelium-dependent vasorelaxation and constitutive NOS expression.
- SNAC effectively prevented plaque development and indicators of endothelial dysfunction in early-stage atherosclerosis.
- SNAC may represent a novel therapeutic strategy for halting the progression of early atherosclerotic plaques.
