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Endothelial alterations in hypercholesterolemia: more than simply vasodilator dysfunction
1Division of Cardiovascular Medicine, Stanford University School of Medicine, California 94305-5406, USA.
Insights
Endothelial dysfunction in vascular disease involves reduced nitric oxide (NO) activity, partly due to elevated ADMA levels. L-arginine supplementation may counteract these effects, offering potential therapeutic strategies for atherosclerosis.
Area of Science:
- Cardiovascular Research
- Endothelial Biology
- Metabolic Disorders
Background:
- Occlusive vascular disease originates from endothelial dysfunction, marked by diminished nitric oxide (NO) activity.
- NO plays a crucial role in inhibiting atherogenesis by regulating monocyte adherence, platelet activation, and smooth muscle proliferation.
- Reduced NO activity in hypercholesterolemia and metabolic disorders is multifactorial, involving free radicals, NO synthase alterations, and endogenous inhibitors like ADMA.
Purpose of the Study:
- To investigate the mechanisms underlying reduced nitric oxide (NO) activity in endothelial dysfunction.
- To explore the role of asymmetric dimethylarginine (ADMA) in hypercholesterolemia and its association with impaired NO-mediated vasodilation.
- To evaluate the potential of L-arginine in counteracting the adverse effects of ADMA.
Main Methods:
- Analysis of factors contributing to decreased NO activity in metabolic disorders.
- Measurement of plasma ADMA concentrations in hypercholesterolemic humans.
- Assessment of endothelium-dependent vasodilation and urinary nitrate excretion.
- Evaluation of the effects of L-arginine administration.
Main Results:
- Plasma ADMA concentrations are elevated in hypercholesterolemic individuals.
- Elevated ADMA is linked to impaired NO-mediated vasodilation and reduced urinary nitrate excretion.
- Administration of the NO precursor L-arginine counteracted the negative effects associated with ADMA.
Conclusions:
- Asymmetric dimethylarginine (ADMA) contributes significantly to endothelial dysfunction in hypercholesterolemia.
- Elevated ADMA levels impair nitric oxide (NO) bioavailability and vasodilation.
- L-arginine shows promise in mitigating ADMA-induced endothelial dysfunction, suggesting potential therapeutic avenues for atherosclerosis.
Abstract:
Occlusive vascular disease begins with an alteration of the endothelium, which is characterized by a decrease in nitric oxide (NO) activity. Endogenous NO inhibits many key processes in atherogenesis, including monocyte adherence, platelet activation, and smooth muscle proliferation. The mechanism by which NO activity is reduced in hypercholesterolemia and in other metabolic disorders associated with atherogenesis appears to be multifactorial. It includes increased production of oxygen-derived free radicals, alterations in NO synthase, and the accumulation of endogenous inhibitors (ADMA) of NO synthase. Plasma concentrations of ADMA are elevated in hypercholesterolemic humans. Elevated ADMA concentrations are associated with impaired endothelium-dependent, NO-mediated vasodilatation and reduced urinary nitrate exertion. These effects of ADMA are counteracted by administration of the NO precursor L-arginine. It is likely that basic insights regarding the mechanisms of endothelial dysfunction will lead to new therapeutic strategies for atherosclerosis.