Testosterone induced downregulation of migration and proliferation in human Umbilical Vein Endothelial Cells by Androgen Receptor dependent and independent mechanisms

Gaba, Aulona; Mairhofer, Mario; Zhegu, Zydi; Leditznig, Nadja; Szabo, Ladislaus; Tschugguel, Walter; Schneeberger, Christian; Yotova, Iveta

doi:10.1016/j.mce.2018.05.007

Cited by 12 publications

(6 citation statements)

References 63 publications

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“…AR then translocates to the nucleus, where it can recruit coactivators and transactivates testosterone-responsive genes by binding to androgen response elements (AREs) in the gene promoters (Shaffer et al, 2004; Burek et al, 2007). Although AR is widely expressed in mammalian cells and tissues, testosterone exerts its pleiotropic effects via AR-dependent or AR-independent mechanisms (Torres-Estay et al, 2017; Gaba et al, 2018). For example, testosterone prevents atherosclerosis through improving endothelial cell growth and survival via AR-independent mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Testosterone Deficiency Caused by Castration Modulates Mitochondrial Biogenesis Through the AR/PGC1α/TFAM Pathway

Liu

Zhang

et al. 2019

Front. Genet.

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Mammalian mitochondrial biogenesis is a complex process involving mitochondrial proliferation and differentiation. Mitochondrial DNA transcription factor A ( TFAM ), which encodes a major component of a protein-mitochondrial DNA (mtDNA) complex, is regulated by peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α). Testosterone is the primary male sex hormone and plays an increasingly important role in mammalian development through its interaction with androgen receptor (AR). However, the function of AR in mitochondrial biogenesis induced by testosterone deficiency has not been investigated. Here, we explored the molecular mechanism underlying the effect of testosterone deficiency on mitochondrial biogenesis using a Yorkshire boar model. Testosterone deficiency caused by castration induced changes in mtDNA copy numbers in various tissues, and AR showed the opposite tendency to that of mtDNA copy number, particularly in adipose tissues and muscle tissues. In addition, castration weakened the correlation of PGC1α and mtDNA copy number, while AR and TFAM showed a relatively high correlation in both control and castrated pigs. Furthermore, luciferase assays revealed that AR binds to potential AR elements in the TFAM promoter to promote TFAM expression. Taken together, testosterone may be involved in the pathway linking PGC1α to mitochondrial biogenesis through the interaction between AR and TFAM .

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Section: Introductionmentioning

confidence: 99%

Testosterone Deficiency Caused by Castration Modulates Mitochondrial Biogenesis Through the AR/PGC1α/TFAM Pathway

Liu

Zhang

et al. 2019

Front. Genet.

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“…Considerable evidence suggests that androgen deficiency was associated with all cardiovascular mortality (Khaw et al, 2007). Furthermore, these were supported by several studies focused on the cardiovascular benefits of testosterone, one of which stimulates nitric oxide synthesis or endothelial progenitor cells (Hotta et al, 2019;Gaba et al, 2018).…”

Section: Resultsmentioning

confidence: 89%

Effect of Diabetes Mellitus on Hypogonadism in Chronic Renal Failure

Karataş¹,

Köse²

2022

Med.Lab.Tech.J.

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Hypogonadism in male patients with chronic renal failure and diabetes mellitus has been known separately; up to now, the effect of these two diseases together on testosterone deficiency and the impact of testosterone deficiency on metabolic values have not been known precisely, therefore in this study we aimed to investigate testosterone deficiency in patients with diabetes mellitus and chronic renal failure. Eighty-seven chronic renal failure patients and 45 control patients who were followed at endocrinology and nephrology clinics were included in the study. After exclusion criteria, the patients were divided into two groups according to diabetes mellitus status. Groups were compared according to testosterone levels. Testosterone deficiency and good groups were compared to blood glucose, Hba1c, and lipid profile levels. The mean age of 87 CRF patients and 45 people in the control group were similar (59.85 ± 9.99 and 56.67 ± 8.56, respectively, p= 0.16). Testosterone deficiency was 24.1% (21/87) in CRF group and 8.8% (4/45) in control group (p= 0.04). The total testosterone levels were notably lower in the diabetic-CRF patients, 3.44 ± 1.3 vs. 4.26 ± 1.46 mg/dl (p= 0.02). The testosterone deficient CRF group had higher blood glucose and HbA1c according to the testosterone sufficient group. (161.20 ± 61.24 mg/dl vs 133.25 ± 59.87 mg/dl blood glucose, p= 0.04 and 7.54 ± 1.46 vs 6.79 ± 1.14 % HbA1c, p= 0.04). Serum triglyceride and LDL levels did not significantly change between groups (p= 0.20 and 0.76, respectively). Testosterone deficiency in male CRF patients is not uncommon. Male patients with both T2DM and CRF have more common testosterone deficiency. In testosterone-sufficient patients, blood glucose regulation was better. Therefore, in these patients, it may be helpful not to neglect testosterone deficiency, which affects gonadal function, body metabolism, and cardiac and skeletal health.

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“…It has been demonstrated that Testo accelerates endothelial cell migration and angiogenesis(40,41). On the other hand, Testo may suppress endothelial cell migration and proliferation(42). Herein, we are describing that Testo induces endothelial cell migration, which is potentiated by NOX4 inhibition.…”

Section: Discussionmentioning

confidence: 99%

NADPH oxidase 4-derived hydrogen peroxide counterbalances testosterone-induced endothelial dysfunction and migration

Alves,

Costa,

Awata

et al. 2023

Preprint

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Background: High levels of testosterone (Testo) are associated with cardiovascular risk by increasing reactive oxygen species (ROS) formation. NADPH oxidases (NOX) are the major source of ROS in the vasculature in cardiovascular diseases. NOX4 is a unique isotype, which produces hydrogen peroxide (H2O2), and its participation in cardiovascular biology is controversial. So far, it is unclear whether NOX4 protects from Testo-induced endothelial injury. Thus, we hypothesized that supraphysiological levels of Testo induce endothelial NOX4 expression to attenuate endothelial injury. Methods: Human Mesenteric Vascular Endothelial Cells (HMEC) and Human Umbilical Vein Endothelial Cells (HUVEC) were treated with Testo (10−7 M) with or without a NOX4 inhibitor [GLX351322 (10-4 M)]. In vivo, 10-week-old C57Bl/6J male mice were treated with Testo (10 mg/kg) for 30 days to study endothelial function. Results: Testo increased mRNA and protein levels of NOX4 in HMEC and HUVEC. Testo increased superoxide anion (O2−) and H2O2 production, which were abolished by NOX1 and NOX4 inhibition, respectively. Testo also attenuated bradykinin-induced NO production, which was further impaired by NOX4 inhibition. In vivo, Testo decreased H2O2 production in aortic segments and triggered endothelial dysfunction [decreased relaxation to acetylcholine (ACh)], which was further impaired by GLX351322 and by a superoxide dismutase and catalase mimetic (EUK134). Finally, Testo led to a dysregulated endothelial cells migration, which was exacerbated by GLX351322. Conclusion: These data indicate that supraphysiological levels of Testo increase the endothelial expression and activity of NOX4 to counterbalance the deleterious effects caused by Testo in endothelial function.

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Testosterone induced downregulation of migration and proliferation in human Umbilical Vein Endothelial Cells by Androgen Receptor dependent and independent mechanisms

Cited by 12 publications

References 63 publications

Testosterone Deficiency Caused by Castration Modulates Mitochondrial Biogenesis Through the AR/PGC1α/TFAM Pathway

Testosterone Deficiency Caused by Castration Modulates Mitochondrial Biogenesis Through the AR/PGC1α/TFAM Pathway

Effect of Diabetes Mellitus on Hypogonadism in Chronic Renal Failure

NADPH oxidase 4-derived hydrogen peroxide counterbalances testosterone-induced endothelial dysfunction and migration

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