Testosterone Protects Against Atherosclerosis in Male Mice by Targeting Thymic Epithelial Cells—Brief Report

Wilhelmson, Anna S.; Rodriguez, Marta Lantero; Eriksson, Elin Svedlund; Johansson, Inger; Fogelstrand, Per; Stubelius, Alexandra; Lindgrén, Susanne; Fagman, Johan Bourghardt; Hansson, Göran; Carlsten, Hans; Karlsson, Mikael C. I.; Ekwall, Olov; Tivesten, Åsa

doi:10.1161/atvbaha.118.311252

Cited by 20 publications

(20 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The male-to-female ratio of mortality from vascular disease is approximately 3:1 worldwide 46 . Previous studies indicate that low level or absent testosterone is associated with an increase in CAD events [18][19][20]47,48 , and testosterone declines with obesity and age 47 . An increase in atherosclerotic plaque deposition was detected in XY mice lacking CYP17A1, and consequently lacking testosterone, suggesting a protective role for this hormone against atherosclerotic plaque formation.…”

Section: Discussionmentioning

confidence: 99%

CYP17A1 deficient XY mice display susceptibility to atherosclerosis, altered lipidomic profile and atypical sex development

Aherrahrou

Kulle

Alenina

et al. 2020

Sci Rep

View full text Add to dashboard Cite

CYP17A1 is a cytochrome P450 enzyme with 17-alpha-hydroxylase and C17,20-lyase activities. CYP17A1 genetic variants are associated with coronary artery disease, myocardial infarction and visceral and subcutaneous fat distribution; however, the underlying pathological mechanisms remain unknown. We aimed to investigate the function of CYP17A1 and its impact on atherosclerosis in mice. At 4-6 months, CYP17A1-deficient mice were viable, with a KO:Het:WT ratio approximating the expected Mendelian ratio of 1:2:1. All Cyp17a1 knockout (KO) mice were phenotypically female; however, 58% were Y chromosome-positive, resembling the phenotype of human CYP17A1 deficiency, leading to 46,XY differences/disorders of sex development (DSD). Both male and female homozygous KO mice were infertile, due to abnormal genital organs. Plasma steroid analyses revealed a complete lack of testosterone in XY-KO mice and marked accumulation of progesterone in XX-KO mice. Elevated corticosterone levels were observed in both XY and XX KO mice. In addition, Cyp17a1 heterozygous mice were also backcrossed onto an Apoe KO atherogenic background and fed a western-type diet (WTD) to study the effects of CYP17A1 on atherosclerosis. Cyp17a1 x Apoe double KO XY mice developed more atherosclerotic lesions than Apoe KO male controls, regardless of diet (standard or WTD). Increased atherosclerosis in CYP17A1 XY KO mice lacking testosterone was associated with altered lipid profiles. In mice, CYP17A1 deficiency interferes with sex differentiation. Our data also demonstrate its key role in lipidomic profile, and as a risk factor in the pathogenesis of atherosclerosis. Coronary artery disease (CAD) is a major cause of morbidity and mortality worldwide 1. Inheritance plays an essential role in the pathogenesis of CAD, and recent genome-wide association studies (GWAS) have revealed more than 160 genomic loci associated with this condition 2. One commonly reported genomic locus, for CAD was located at chr10p24.32. The same locus is also associated with myocardial infarction (MI) 3 and visceral and subcutaneous fat distribution 4. This locus harbors the CYP17A1 gene, which encodes the cytochrome P450 17A1 enzyme, also referred to as steroid 17-alpha-monooxygenase or 17α-hydroxylase/17,20-lyase/17,20-desmolase.

show abstract

Section: Discussionmentioning

confidence: 99%

CYP17A1 deficient XY mice display susceptibility to atherosclerosis, altered lipidomic profile and atypical sex development

Aherrahrou

Kulle

Alenina

et al. 2020

Sci Rep

View full text Add to dashboard Cite

show abstract

“…G-ARKO and E-ARKO male mice were generated as previously described (17,20). T-ARKO and E-ARKO male mice were generated by breeding AR +/flox female mice with male pLCK-Cre + mice (Stock no.…”

Section: Methods Animalsmentioning

confidence: 99%

Androgen Receptors in Epithelial Cells Regulate Thymopoiesis and Recent Thymic Emigrants in Male Mice

et al. 2020

Self Cite

View full text Add to dashboard Cite

“…The incidence rates of hypertension and coronary artery disease have long been known to be higher in men than in women [18][19][20] , but only recently has evidence begun to accumulate indicating that low concentrations of androgens are associated with vascular injury. Notably, male patients receiving androgen deprivation therapy have an increased risk of cardiovascular disease 21 , while exogenous testosterone supplementation protects cardiac myocytes 22 . Experiments in male mice showed that testosterone protects against atherosclerosis by targeting thymic epithelial cells 21 .…”

Section: Discussionmentioning

confidence: 99%

“…Notably, male patients receiving androgen deprivation therapy have an increased risk of cardiovascular disease 21 , while exogenous testosterone supplementation protects cardiac myocytes 22 . Experiments in male mice showed that testosterone protects against atherosclerosis by targeting thymic epithelial cells 21 . In addition, androgens were shown to play an antihypertensive role in spontaneously hypertensive rats, while androgen de ciency could trigger the development of hypertension 23 .…”

Section: Discussionmentioning

confidence: 99%

Androgens deficiency impairs thoracic aortic vascular function by promoting smooth muscle cell proliferation via an autophagy dependent manner

Zhang

Gao

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Androgens play an essential role in maintaining vascular hemostasis via the regulation of autophagy, but the underlying mechanisms remain unknown. Here we investigated the effects of androgen deficiency in a rat castration model and the effects of androgen treatment in human umbilical vein smooth muscle cells (HUVSMCs). Male Sprague–Dawley rats were divided into two groups: (A) control group, (B) castration group. The vasodilation and vasoconstriction effect of dihydrotestosterone (DHT) were detected on rat thoracic aortic rings. Transmission electron microscopy was used to determine the levels of autophagy. Masson’s trichrome staining, MTT assay and flow cytometry were performed to detect the levels of HUVSMC cell proliferation. Results Androgen deficiency led to significantly enhance in the vasoconstriction and reductions in the vasodilatation of rat thoracic aortic rings. Treatment with rapamycin or 3-MA attenuated and enhanced, respectively, the vasorelaxation effect of androgen deficiency. Autophagy was significantly increased in the endothelial cells and SMCs of the thoracic aortic rings of model rats. Moreover, androgen deficiency induced excessive proliferation of SMCs. Treatment of HUVMSCs with high concentrations of DHT increased the percentage of cells in G0/G1 phase and reduced the percentages of cells in the G2 phase and S phase. Conclusions It was concluded that vascular injury resulting from androgen deficiency is mediated, in part, by increased autophagy. By promoting SMCs proliferation, androgen deficiency results in alteration of the aortic structure and aggravates vascular injury. Androgen treatment can inhibit the excessive proliferation of SMCs.

show abstract

Testosterone Protects Against Atherosclerosis in Male Mice by Targeting Thymic Epithelial Cells—Brief Report

Abstract: Supplemental Digital Content is available in the text.

Cited by 20 publications

References 39 publications

CYP17A1 deficient XY mice display susceptibility to atherosclerosis, altered lipidomic profile and atypical sex development

CYP17A1 deficient XY mice display susceptibility to atherosclerosis, altered lipidomic profile and atypical sex development

Androgen Receptors in Epithelial Cells Regulate Thymopoiesis and Recent Thymic Emigrants in Male Mice

Androgens deficiency impairs thoracic aortic vascular function by promoting smooth muscle cell proliferation via an autophagy dependent manner

Contact Info

Product

Resources

About