Abstract
The studies on hormone replacement therapy (HRT) in females with estrogen deficiency are not conclusive. Thus, non-estrogen therapies, such as atorvastatin (ATO), could be new strategies to substitute or complement HRT. This study evaluated the effects of ATO on mesenteric vascular bed (MVB) function from ovariectomized (OVX) female rats. Female rats were divided into control SHAM, OVX, and OVX treated with 17β-estradiol (EST) or ATO groups. The MVB reactivity was determined in organ chambers, vascular oxidative stress by dihydroethidine staining, and the expression of target proteins by western blot. The reduction in acetylcholine-induced relaxation in OVX rats was restored by ATO or EST treatment. The endothelium-dependent nitric oxide (NO) component was reduced in OVX rats, whereas the endothelium-derived hyperpolarizing factor (EDHF) component or prostanoids were not altered in the MVBs. Endothelial dysfunction in OVX rats was associated with oxidative stress, an up-regulation of iNOS and NADPH oxidase expression and a down-regulation of eNOS expression. Treatment with ATO or EST improved the NO component of the relaxation and normalized oxidative stress and the expression of those signaling pathways enzymes. Thus, the protective effect of ATO on endothelial dysfunction caused by estrogen deficiency highlights a significant therapeutic benefit for statins independent of its effects on cholesterol, thus providing evidence that non-estrogen therapy could be used for cardiovascular benefit in an estrogen-deficient state, such as menopause.
Highlights
The role of estrogens in vascular function has received considerable research interest because epidemiological studies have shown a greater risk of developing cardiovascular disease (CVD) due to reduced 17β-estradiol levels after menopause [1,2,3]
The present study indicates that the treatment with atorvastatin is sufficient to reverse the endothelial dysfunction observed in female rats with estrogen deficiency
Our major novel finding is demonstrating that increased reactive oxygen species (ROS) production, NADPH oxidase and inducible NO synthase (iNOS) overexpression and reduced eNOS expression in OVX mesenteric vessels, which can lead to reduced nitric oxide (NO) availability, were restored by atorvastatin and estrogen replacement
Summary
The role of estrogens in vascular function has received considerable research interest because epidemiological studies have shown a greater risk of developing cardiovascular disease (CVD) due to reduced 17β-estradiol levels after menopause [1,2,3]. The main mechanisms involved in the impaired vascular response in estrogen deficiency models are connected decreased nitric oxide (NO) bioavailability and the attenuation of hyperpolarization and relaxation transduced by endotheliumderived hyperpolarizing factor (EDHF) [6,7,8]. The risk of the development of diabetes in patients with impaired fasting glucose, metabolic syndrome or severe obesity was reported by some statin therapy studies [12,13]. These side effects do not exceed the benefits promoted by the hypercholesterolemia therapy [14,15]. Even postmenopausal patients show a significant reduction of atherosclerosis after being treated with statins [16,17]
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