Tamoxifen up-regulates catalase production, inhibits vessel wall neutrophil infiltration, and attenuates development of experimental abdominal aortic aneurysms

Grigoryants, Vladimir; Hannawa, Kevin K.; Pearce, Charles G.; Sinha, Indranil; Roelofs, Karen J.; Ailawadi, Gorav; Deatrick, Kristopher B; Woodrum, Derek T.; Cho, Brenda S.; Henke, Peter K.; Stanley, James C.; Eagleton, Matthew J.; Upchurch, Gilbert R.

doi:10.1016/j.jvs.2004.09.033

Cited by 57 publications

(39 citation statements)

References 28 publications

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“…Tamoxifen is a selective estrogen receptor modulator that can act as either antagonist or agonist to estrogen, depending on types of organs. In an enzymatic destruction model, it has been shown that tamoxifen ameliorates the aneurysmal pathology via a mechanism similar to exogenous estrogen (15). Such an off-target effect of the tamoxifen seems not a dominant factor in our model since aortic pathology still occurred in ovariectomized females while absent in females with intact ovaries following tamoxifen administration.…”

Section: Discussionmentioning

confidence: 81%

Hypertension overrides the protective effect of female hormones on the development of aortic aneurysm secondary to Alk5 deficiency via ERK activation

Schmit

Yang

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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The prevalence of aortic aneurysm is five times higher in men than women among the general population. Similar sexual dimorphism also exists in syndromic aortic aneurysms triggered by TGF-β signaling disorders. To understand the responsible mechanisms, we developed an animal model where inducible deletion of the type I TGF-β receptor, Alk5, specifically in smooth muscle cells ( Alk5 iko) causes spontaneous aortic aneurysm formation. This model recapitulated an extreme scenario of the dimorphism in aortic aneurysm development between genders. In a comparative experiment, all Alk5 iko males ( n = 42) developed aortic aneurysms and 26% of them died prematurely from aortic rupture. In contrast, the Alk5 iko females ( n = 14) presented only a subclinical phenotype characteristic of scarcely scattered elastin breaks. Removal of male hormones via orchiectomy ( n = 7) resulted in only minimal influence on aortic pathology. However, reduction of female hormones via ovariectomy ( n = 15) increased the phenotypic penetrance from zero to 53%. Finally, an elevation of systolic blood pressure by 30 points unmasked the subclinical phenotype of Alk5 iko females ( n = 17) to 59%. This exaggerated phenotypic penetrance was coupled with an early intensification of ERK signaling, a molecular signature that correlated to 100% phenotypic penetrance in normotensive Alk5 iko males. In conclusion, aortic aneurysm induced by Alk5 iko exhibits dimorphic incidence between genders with females less susceptible to aortic disease. This sexual dimorphism is partially the result from the protective effects of female hormones. Hypertension, a known risk factor for aortic aneurysm, is able to break the female sex protective effects through mechanisms associated with enhanced ERK activity.

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Section: Discussionmentioning

confidence: 81%

Hypertension overrides the protective effect of female hormones on the development of aortic aneurysm secondary to Alk5 deficiency via ERK activation

Schmit

Yang

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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“…It is conceivable that one could design SERMs that would retain the desired effects of estrogen to targeted tissues but devoid of the undesirable effects (39). In one study SERM attenuated the development of experimental aneurysms (40). Phytoestrogens are estrogenic compounds of plant origin classified into different groups with There are a number of limitations of our study.…”

Section: Discussionmentioning

confidence: 96%

A higher aneurysmal subarachnoid hemorrhage incidence in women prior to menopause: a retrospective analysis of 4,895 cases from eight hospitals in China

Wáng

Zhang

et al. 2016

Quant. Imaging Med. Surg.

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Background: Subarachnoid hemorrhage (SAH) from a ruptured cerebral aneurysm is a devastating disease.Despite the risk factors, including hypertension, cigarette smoking and alcohol use, are more common in men, aneurysmal SAH belongs to a few diseases which the incidence is higher in women than in men. Sex hormones, especially estrogen, might be protective against this condition. Hormone replacement therapy (HRT) seems to be associated with a reduced risk for aneurysmal SAH. This study aims to know the prevalence of aneurysmal SAH of men and women at different ages. Methods:The age and gender information of 4,895 case of aneurysmal SAH (3,016 females, 1,879 males) were collected retrospectively from eight institutions in mainland China. The prevalence of aneurysmal SAH of men and women at different ages was analyzed.Results: The data showed women had a higher incidence of aneurysmal SAH than men starting at late thirties, and men might have a higher incidence of aneurysmal SAH than women only before 37-year-old.Conclusions: Menopause may not be the only dominant factor causing higher incidence of aneurysmal SAH in women than in men. Quant Imaging Med Surg 2016;6(2):151-156 qims.amegroups.com the short-term and long-term risks of aneurysmal rupture with the risk associated with the intervention, whether it would be surgical clipping or endovascular management. Controversy remains regarding optimum management, and thorough assessments of the risks and benefits of contemporary management options, specific to aneurysm size, location, and many other aneurysm and patient factors, are needed. Endovascular management options continue to improve as micro-catheter technology advances and newer devices and embolic materials are developed. The most commonly used endovascular option is the Guglielmi detachable coil system. This system allows delivery of soft platinum coils into intracranial aneurysms. Overall, clinical trial data showed better recovery data with patients treated endovascularly than treated surgically (3). Findings from several studies also suggested that cerebral aneurysm rupture risk is reduced in patients taking aspirin (4). Recent data support long-term serial screening in individuals with a family history of aneurysmal SAH (5).Despite the risk factors, including hypertension, cigarette smoking and alcohol use, are more common in men, aneurysmal SAH belongs to a few diseases which the incidence is higher in women than in men (1-3,6,7). Women have a significantly higher risk for de novo cerebral aneurysm formation than men in a long-term follow-up study, being female is a significant independent risk factor for aneurysm growth; and women are more likely than men to have multiple cerebral aneurysms (7-9). It has been noted that the incidence was higher in younger men, whereas after the age of 55, the incidence was higher in women (2). Furthermore, earlier age at menopause may be associated with a greater risk of cerebral aneurysm (10). Therefore, a sex-specific hormonal factor may play a role in the pathogen...

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“…In another AAA study, tamoxifen, a selective estrogen receptor modulator, decreased neutrophil infiltration and increased catalase expression. 72 Catalase is an antioxidative enzyme involved on hydrogen peroxide metabolism and can block the activation of MMP2 in SMCs. 72 Finally, dietary phytoestrogens inhibited experimental AAA formation in male mice through a reduction of the inflammatory response in the aortic wall.…”

Section: Exogenous Estrogens In Aaamentioning

confidence: 99%

“…72 Catalase is an antioxidative enzyme involved on hydrogen peroxide metabolism and can block the activation of MMP2 in SMCs. 72 Finally, dietary phytoestrogens inhibited experimental AAA formation in male mice through a reduction of the inflammatory response in the aortic wall. 73 The Role of Exogenous Testosterone in AAA Development…”

Section: Exogenous Estrogens In Aaamentioning

confidence: 99%

Sex Differences in Abdominal Aortic Aneurysm: The Role of Sex Hormones

Makrygiannis

Courtois

Drion

et al. 2014

Annals of Vascular Surgery

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Abdominal aortic aneurysm (AAA) is a complex multifactorial disease with genetic and environmental components. AAA is more common in men, whereas women have a greater risk of rupture and more frequently have concomitant thoracic aortic aneurysms. Moreover, women are diagnosed with AAA about 10 years later and seem to be protected by female sex hormones. In this MEDLINE-based review of literature, we examined human and animal in vivo and in vitro studies to further deepen our understanding of the sexual dimorphism of AAA. We focus on the role of sex hormones during the formation and growth of AAA. Endogenous estrogens and exogenous 17b-estradiol were found to exert favorable actions protecting from AAA in animal models, whereas exogenous hormone replacement therapy in humans had inconclusive results. Androgens, known to have detrimental effects in the vasculature, in sufficient levels maintain the integrity of the aortic wall through their anabolic actions and act differentially in men and women, whereas lower levels of testosterone have been associated with AAA in humans. In conclusion, sex differences remain an important area of AAA research, but further studies especially in humans are needed. Furthermore, differential molecular mechanisms of sex hormones constitute a potential therapeutic target for AAA.

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Tamoxifen up-regulates catalase production, inhibits vessel wall neutrophil infiltration, and attenuates development of experimental abdominal aortic aneurysms

Abstract: The selective estrogen receptor modulator tamoxifen inhibits the development of AAAs in male rats in association with an up-regulation of catalase and inhibition of aortic wall neutrophil infiltration.

Cited by 57 publications

References 28 publications

Hypertension overrides the protective effect of female hormones on the development of aortic aneurysm secondary to Alk5 deficiency via ERK activation

Hypertension overrides the protective effect of female hormones on the development of aortic aneurysm secondary to Alk5 deficiency via ERK activation

A higher aneurysmal subarachnoid hemorrhage incidence in women prior to menopause: a retrospective analysis of 4,895 cases from eight hospitals in China

Sex Differences in Abdominal Aortic Aneurysm: The Role of Sex Hormones

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