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Cardiovascular Research 2007 73(1):66-72; doi:10.1016/j.cardiores.2006.09.020
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Copyright © 2006, European Society of Cardiology

Estradiol counteracts oxidized LDL-induced asymmetric dimethylarginine production by cultured human endothelial cells

Elena Monsalvea, Pilar J. Oviedob, Miguel Angel García-Pérezc, Juan J. Tarínd, Antonio Canob and Carlos Hermenegildoa,c,*

aDepartment of Physiology, University of Valencia, Spain
bDepartment of Pediatrics, Obstetrics and Gynaecology, University of Valencia, Spain
cResearch Foundation, Hospital Clínico Universitario, Valencia, Spain
dDepartment of Functional Biology and Physical Anthropology, University of Valencia, Spain

* Corresponding author. Research Foundation, Hospital Clínico Universitario de Valencia, Av. Blasco Ibañez, 17, E 46010 Valencia, Spain. Tel.: +34 96 3864900; fax: +34 96 3864815. Email address: carlos.hermenegildo{at}uv.es

Objective: Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthase, is a novel cardiovascular risk factor produced by endothelial cells. ADMA levels are mainly regulated by the activity of dimethylarginine dimethylaminohydrolases (DDAH). Endothelial release of ADMA is increased in the presence of oxidized LDL cholesterol (oxLDL), whereas estrogens stimulate NO production by endothelial cells by increasing both expression and activity of NO synthase and by reducing ADMA levels. Thus, the aim of the present study was to evaluate the estradiol effects on the DDAH/ADMA/NO pathway in cultured human umbilical vein endothelial cells (HUVEC) exposed to LDL.

Methods: After 24 h of exposure to various treatments, culture medium was collected to measure NO production by using an amperometric sensor specific for NO, and to measure dimethylarginines by high-performance liquid chromatography (HPLC). DDAH-I and II mRNA expression and protein content were quantified by real-time PCR assay and immunoblotting, respectively.

Results: Exposure of HUVEC to 100 µg/mL oxLDL, but not to 100 µg/mL of native LDL (nLDL), reduced DDAH-II expression at both the mRNA as well as the protein levels, which in turn increased ADMA levels and reduced NO production. Estradiol (1 nM) alone increased DDAH-II mRNA and protein expression, which reduced ADMA levels and increased NO production. In cells exposed to estradiol in combination with either nLDL or oxLDL, levels of DDAH-II, ADMA, and NO were the same as those for estradiol alone.

Conclusion: Estradiol completely reverses the effects induced by oxLDL on the DDAH/ADMA/NO pathway.

KEYWORDS Cholesterol; Endothelial function; Estrogens; Nitric oxide

Time for primary review 37 days


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