Effects of androgens on cardiovascular remodeling

Ikeda, Yasumasa; Aihara, Ken‐ichi; Yoshida, Sumiko; Akiyama, Masashi; Matsumoto, Toshio

doi:10.1530/joe-12-0126

Cited by 26 publications

(17 citation statements)

References 103 publications

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“…75 Despite the many detrimental effects of testosterone, some studies revealed that androgens exert atheroprotective effects against cardiovascular disease at least in the elderly people, mediated by the androgen receptors. 85 Besides, lower levels of testosterone had harmful effect on AAA and on the cardiovascular system in men. 23 In conclusion, there are still many controversies and unanswered questions about the sex differences in AAA.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Our observation that DHT induces both VEGF and NO suggests that the pro-angiogenic effects of DHT may be mediated via a cross-talk between them. Moreover, this may create a synergistic environment as VEGF has been shown to induce angiogenesis via NO generation and NO induces VEGF thereby creating a positive feedback angiogenic loop (Papapetropoulos et al 1997, Losordo & Isner 2001, Ikeda et al 2012.…”

Section: Journal Of Molecular Endocrinologymentioning

confidence: 99%

Dihydrotestosterone induces pro-angiogenic factors and assists homing of MSC into the cardiac tissue

Popa

Mihai

Constantin

et al. 2018

Journal of Molecular Endocrinology

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The use of mesenchymal stem cells (MSC) as a therapeutic tool in cardiovascular diseases is promising. Since androgens exert some beneficial actions on the cardiovascular system, we tested our hypothesis that this hormone could promote MSC-mediated repair processes, also. Cultured MSCs isolated from Wharton's jelly were exposed to 30 nM dihydrotestosterone (DHT) for 1 or 4 days and the effects of the hormone on their growth/migration/adhesion and the underlying mechanisms were assessed. Results were obtained by real-time cell impedance measurements, and DNA quantification showed that DHT increased MSC proliferation by ~30%. As determined by xCELLigence system, DHT augmented (~2 folds) the migration of MSC toward cardiac tissue slices (at 12 h), and this effect was blocked by flutamide, an androgen receptor (AR) antagonist. Exposure of cells to DHT, upregulated the gene and protein expression of , and and downregulated the expression of DHT significantly induced the release of nitric oxide by MSC (≥2-fold) and flutamide blocked this effect. When MSCs were co-cultured with cardiac slices, immunohistochemical analysis and qRT-PCR showed that the integration of DHT-stimulated MSC was significantly higher than that of in controls. In conclusion, our findings provide the first evidence that DHT promotes MSC growth, migration and integration into the cardiac slices. The modulating effects of DHT were associated with upregulation of ARs and of key molecules known to promote tissue remodeling and angiogenesis. Our findings suggest that priming of MSC with DHT may potentially increase their capability to regenerate cardiac tissue; studies are needed to confirm our findings.

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“…Functional effects are elicited once AR is activated either directly or indirectly by interaction with specific coactivator proteins that regulate transcriptional responses [40]. In addition, current evidence indicates that testosterone activity is regulated through both AR-dependent and -independent mechanisms [9, 41]. NFAT/calcineurin signaling has been well established as a regulator of hypertrophic growth, and we here provide new insights regarding the mechanisms implicated in cardiac myocyte hypertrophy induced by testosterone.…”

Section: Discussionmentioning

confidence: 91%

GSK-3β/NFAT Signaling Is Involved in Testosterone-Induced Cardiac Myocyte Hypertrophy

et al. 2016

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Testosterone induces cardiac hypertrophy through a mechanism that involves a concerted crosstalk between cytosolic and nuclear signaling pathways. Nuclear factor of activated T-cells (NFAT) is associated with the promotion of cardiac hypertrophy, glycogen synthase kinase-3β (GSK-3β) is considered to function as a negative regulator, mainly by modulating NFAT activity. However, the role played by calcineurin-NFAT and GSK-3β signaling in testosterone-induced cardiac hypertrophy has remained unknown. Here, we determined that testosterone stimulates cardiac myocyte hypertrophy through NFAT activation and GSK-3β inhibition. Testosterone increased the activity of NFAT-luciferase (NFAT-Luc) in a time- and dose-dependent manner, with the activity peaking after 24 h of stimulation with 100 nM testosterone. NFAT-Luc activity induced by testosterone was blocked by the calcineurin inhibitors FK506 and cyclosporine A and by 11R-VIVIT, a specific peptide inhibitor of NFAT. Conversely, testosterone inhibited GSK-3β activity as determined by increased GSK-3β phosphorylation at Ser9 and β-catenin protein accumulation, and also by reduction in β-catenin phosphorylation at residues Ser33, Ser37, and Thr41. GSK-3β inhibition with 1-azakenpaullone or a GSK-3β-targeting siRNA increased NFAT-Luc activity, whereas overexpression of a constitutively active GSK-3β mutant (GSK-3βS9A) inhibited NFAT-Luc activation mediated by testosterone. Testosterone-induced cardiac myocyte hypertrophy was established by increased cardiac myocyte size and [3H]-leucine incorporation (as a measurement of cellular protein synthesis). Calcineurin-NFAT inhibition abolished and GSK-3β inhibition promoted the hypertrophy stimulated by testosterone. GSK-3β activation by GSK-3βS9A blocked the increase of hypertrophic markers induced by testosterone. Moreover, inhibition of intracellular androgen receptor prevented testosterone-induced NFAT-Luc activation. Collectively, these results suggest that cardiac myocyte hypertrophy induced by testosterone involves a cooperative mechanism that links androgen signaling with the recruitment of NFAT through calcineurin activation and GSK-3β inhibition.

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Effects of androgens on cardiovascular remodeling

Cited by 26 publications

References 103 publications

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

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

Dihydrotestosterone induces pro-angiogenic factors and assists homing of MSC into the cardiac tissue

GSK-3β/NFAT Signaling Is Involved in Testosterone-Induced Cardiac Myocyte Hypertrophy

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