Dehydroepiandrosterone protects against oxidative stress-induced endothelial dysfunction in ovariectomized rats.

Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of S˜ao Paulo, SP, Brazil.
The Journal of Physiology (Impact Factor: 4.38). 05/2011; 589(Pt 10):2585-96. DOI: 10.1113/jphysiol.2011.206078
Source: PubMed

ABSTRACT Cardiovascular disease is less frequent in premenopausal women than in age-matched men or postmenopausal women. Moreover, the marked age-related decline in serum dehydroepiandrosterone (DHEA) level has been associated to cardiovascular disease. The aim of this study was to evaluate the effects of DHEA treatment on vascular function in ovariectomized rats. At 8 weeks of age, female Wistar rats were ovariectomized (OVX) or sham (SHAM) operated and 8 weeks after surgery both groups were treated with vehicle or DHEA (10mg kg⁻¹ week⁻¹) for 3 weeks. Aortic rings were used to evaluate the vasoconstrictor response to phenylephrine (PHE) and the relaxation responses to acetylcholine (ACh) and sodium nitroprusside (SNP). Tissue reactive oxygen species (ROS) production and SOD, NADPH oxidase and eNOS protein expression were analysed. PHE-induced contraction was increased in aortic rings from OVX compared to SHAM, associated with a reduction in NO bioavailability. Furthermore, the relaxation induced by ACh was reduced in arteries from OVX, while SNP relaxation did not change. The incubation of aortic rings with SOD or apocynin restored the enhanced PHE-contraction and the impaired ACh-relaxation only in OVX. DHEA treatment corrected the increased PHE contraction and the impaired ACh-induced relaxation observed in OVX by an increment in NO bioavailability and decrease in ROS production. Besides, DHEA treatment restores the reduced Cu/Zn-SOD protein expression and eNOS phosphorylation and the increased NADPH oxidase protein expression in the aorta of OVX rats. The present results suggest an important action of DHEA, improving endothelial function in OVX rats by acting as an antioxidant and enhancing the NO bioavailability.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Tardive dyskinesia (TD) is a potentially irreversible consequence of long term treatment with antipsychotic drugs which is according to a well-known theory believed to be related to oxidative stress induced neurotoxicity. Dehydroepiandrosterone (DHEA) is an endogenous antioxidant with neuroprotective activity. The biosynthesis of DHEA depends upon the activity of cytochrome P450c17α (CYP17). The gene that encodes for CYP17 has a (T34C) single nucleotide polymorphism which enhances CYP17 transcription and expression. To test the hypothesis that carriership of a more active CYP17 variant would result in higher DHEA(S) levels and protect against neurotoxicity which results in orofaciolingual TD (TDof), limb-truncal TD (TDlt) or both (TDsum)? Tardive dyskinesia was assessed cross-sectionally in 146 Caucasian psychiatric inpatients from Siberia. Patients who are carriers of the Cyp17 genotype CC have less chance of developing TD compared to patients who are carriers of the Cyp17 genotypes TC or TT (p<0.05). However, these carriers have significant lower circulating DHEAS levels compared to carriers of the Cyp17 genotypes TC and TT (p<0.05). Conversely, carriers of the CYP17 T-allele have significant elevated DHEAS levels. After correcting for gender and age no significant relationship between Cyp17 genotype CC, the T-allelle and the C-allele and the DHEAS concentration of patients was observed. Conclusions: Although an association between the CYP17 CC genotype and TD is indicated, our findings do not support the hypothesis that this is mediated through increased DHEA(S) levels. We believe that the relationship between this polymorphism and neuroprotective effects of steroids is more complex and cannot be elucidated without taking the posttranslational regulation of the enzyme into account.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 01/2014; · 3.55 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Dehydroepiandrosterone (DHEA) and the dehydroepiandrosterone sulfate (DHEA-S) are steroids produced mainly by the adrenal cortex. There is evidence from both human and animal models suggesting beneficial effects of these steroids for obesity, diabetes mellitus, hypertension, and osteoporosis, conditions associated with the post-menopausal period. Accordingly, we hypothesized that DHEA supplementation in ovariectomized (OVX) female rats fed a high-fat diet would maintain glucose-induced insulin secretion (GSIS) and pancreatic islet function. OVX resulted in a 30% enlargement of the pancreatic islets area compared to the control rats, which was accompanied by a 50% reduction in the phosphorylation of AKT protein in the pancreatic islets. However, a short-term high-fat diet induced insulin resistance, accompanied by impaired GSIS in isolated pancreatic islets. These effects were reversed by DHEA treatment, with improved insulin sensitivity to levels similar to the control group, and with increased serine phosphorylation of the AKT protein. These data confirm the protective effect of DHEA on the endocrine pancreas in a situation of diet-induced overweight and low estrogen concentrations, a phenotype similar to that of the post-menopausal period.
    FEBS Open Bio. 01/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Metformin is an antihyperglycaemic drug with pleiotropic effects that result in cardiovascular improvement. This study aimed to evaluate the effects of metformin (MET) treatment on vascular dysfunction in ovariectomized (OVX) rats. Methods: At 8 weeks old, female Wistar rats were subjected to ovariectomy or a sham surgery (SHAM). After 21 days, the animals were divided into three groups, the SHAM (control), OVX and MET (treated OVX rats, 300 mg/kg/day) groups, and treated for 14 days. The acetylcholine (ACh) and sodium nitroprusside (SNP) vasorelaxation responses were evaluated in mesenteric vascular beds, oxidative stress was evaluated and western blot analyses of eNOS and the NADPH oxidase was performed. Results: ACh-induced relaxation was reduced in OVX rats and partially restored in MET rats. L-NAME attenuated and equalised the ACh-induced response in all groups. The attenuation of the ACh-induced responses by 4-aminopyridine (a blocker of voltage-gated potassium channels) was greater in MET rats. The SNP-induced responses were reduced in OVX rats and restored in MET rats. The inhibition of NADPH oxidase by apocynin (10 μM) restored the SNP-induced responses in OVX rats, enhanced these responses in MET rats and had no effect in SHAM rats. OVX rats exhibited reduced levels of eNOS protein and increased levels of oxidative stress and Nox2 protein; metformin treatment corrected all of these parameters. Conclusions: The pathophysiological changes observed in the mesenteric beds of OVX rats were ameliorated by metformin. If this translates to humans, metformin would have additional benefits for postmenopausal women treated with this drug for glycaemic control.
    Clinical Science 02/2014; · 4.86 Impact Factor

Full-text (2 Sources)

Available from
May 20, 2014

Similar Publications