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: 5.04). 05/2011; 589(Pt 10):2585-96. DOI: 10.1113/jphysiol.2011.206078
Source: PubMed


Non-technical summary It is well known that cardiovascular disease is more frequent in postmenopausal than in premenopausal women. Moreover, it has been shown that dehydroepiandrosterone (DHEA), a steroid hormone secreted by adrenal glands, reduces during ageing. Its reduced plasma level has been related to increased prevalence of obesity, insulin resistance and cardiovascular disease. We show that DHEA treatment in ovariectomized rats, an experimental model of menopause, reduces blood pressure and improves vascular function. Furthermore, DHEA reduced reactive oxygen species (ROS), correcting the reduced protein expression of Cu/Zn-SOD, an antioxidant protein, and increased protein expression of NADPH oxidase, a pro-oxidant protein. This work shows the potential effect of DHEA upon correction of endothelial dysfunction observed on oestrogen deprivation.
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 (10 mg 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.

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    • "One of these substances is dehydroepiandrosterone (DHEA), which is together with its sulfate ester (DHEAS) one of the most abundant steroids in the human body. Both DHEA and DHEAS have antioxidant effects (Camporez et al., 2011; Gao et al., 2005; Maninger et al., 2009). Evidence also indicates that DHEA and DHEAS are synthesized in the brain (Maninger et al., 2009). "
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    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.
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    • "This impaired vascular response may occur in long-term (ovariectomy) and short-term (diestrous cycle) estrogen-deficient states [6]. In addition, impaired endothelial function in ovariectomized rats was associated with an increase in superoxide anion production and the increased protein expression of NADPH oxidase subunits, as gp91phox and p22phox [9,10]. "
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    • "Chronic angiotensin II type 1 receptor (AT1) blockade significantly reduces blood pressure in postmenopausal women (Fernandez-Vega et al., 2002). In female rats, estrogen deprivation by bilateral OVX causes arterial hypertension and myocardial dysfunction (Camporez et al., 2011; Ribeiro et al., 2012), that are partially attributed to angiotensin-converting enzyme (ACE) overactivity and significant increases in the AT1 receptor expression in the heart, kidney and vessels (Dean et al., 2005). Changes in urinary patterns also occur as a consequence of menopause (Melby et al., 2005; Nelson, 2008). "
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