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Review
. 2017 Jul 1;131(13):1405-1418.
doi: 10.1042/CS20170090.

Genomic and non-genomic effects of androgens in the cardiovascular system: clinical implications

Angela K Lucas-Herald  1   2 , Rheure Alves-Lopes  2 , Augusto C Montezano  2 , S Faisal Ahmed  1 , Rhian M Touyz  3
Affiliations
Review

Genomic and non-genomic effects of androgens in the cardiovascular system: clinical implications

Angela K Lucas-Herald et al. Clin Sci (Lond). .

Abstract

The principle steroidal androgens are testosterone and its metabolite 5α-dihydrotestosterone (DHT), which is converted from testosterone by the enzyme 5α-reductase. Through the classic pathway with androgens crossing the plasma membrane and binding to the androgen receptor (AR) or via mechanisms independent of the ligand-dependent transactivation function of nuclear receptors, testosterone induces genomic and non-genomic effects respectively. AR is widely distributed in several tissues, including vascular endothelial and smooth muscle cells. Androgens are essential for many developmental and physiological processes, especially in male reproductive tissues. It is now clear that androgens have multiple actions besides sex differentiation and sexual maturation and that many physiological systems are influenced by androgens, including regulation of cardiovascular function [nitric oxide (NO) release, Ca2+ mobilization, vascular apoptosis, hypertrophy, calcification, senescence and reactive oxygen species (ROS) generation]. This review focuses on evidence indicating that interplay between genomic and non-genomic actions of testosterone may influence cardiovascular function.

Keywords: androgen receptor; cardiovascular; genomic; non-genomic.

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Conflict of interest statement

The authors declare that there are no competing interests associated with the manuscript.

Figures

Figure 1
Figure 1. DNA binding-dependent signalling induced by androgens
(1) The genomic AR signalling involves androgen crossing the plasma membrane, entering the cytoplasm, dissociation of chaperone proteins and binding to the AR. (2) Testosterone induced-ROS generation is followed by an increase in Nox1 and Nox4 mRNA levels and p47phox protein expression. (3) Gas6 signalling induced by testosterone is mediated by phosphorylation of the PI3K/Akt pathway, and an increase of anti-apoptotic Bcl2 family proteins. (4) Hypertrophy induced by testosterone involves recruitment of NFAT through calcineurin activation and GSK-3β inhibition. (5) Testosterone down-regulates the AT2R receptor via AR-mediated ERK1/2 activation. (6) Hypogonadism is shown to decrease nNOS and α-actin expression and increase p38 phosphorylation and caspase 3 cleavage. (7) Testosterone stimulation results in a concurrent increase in the production of H2S, and consequently vasodilation via TRPV4 and large-conductance Ca2+-activated K-channels.
Figure 2
Figure 2. Non-DNA binding-dependent signalling induced by androgens
(1) Testosterone via rapid response activates PLC, IP3 and DAG and initiates intracellular calcium release and PKC activation. (2) Via binding to GPRC6A, testosterone leads to ERK phosphorylation by mechanisms involving PI3K, PKC and Src. (3) GPRC6A mediates the non-genomic effects of testosterone on intracellular calcium mobilization and H2O2 through Duox1. (4) ZIP9 activation induced by testosterone is involved in testosterone induced ERK1/2, CREB and pATF-1 phosphorylation. (5) Via interaction with AR, androgens activate L-type calcium channels, which increase the intracellular levels of calcium, activate PKC, and via calmodulin activate PKA and MAPK pathways. (6) Activation of PI3k/Akt signalling and the direct interaction of AR with p85α/c-Src/caveolin1 are involved in testosterone-induced eNOS phosphorylation. (7) Testosterone increases mitochondrial-ROS generation and procaspase-8 and -3 activation in VSMC, an effect followed by reduction of O2 consumption, increased expression of death receptors and apoptosis. (8) Rapid generation of ROS induced by testosterone involves NAPH oxidase activation. (9) Androgen binding to TRPM8 is followed by an increase in TRPM8-induced increase in intracellular levels of Ca2+.
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References

    1. Freeman B.M., Univers J., Fisher R.K.. et al. (2017) Testosterone replacement attenuates intimal hyperplasia development in an androgen deficient model of vascular injury. J. Surg. Res. 207, 53–6210.1016/j.jss.2016.08.016 - DOI - PubMed
    1. Comeglio P., Cellai I., Filippi S.. et al. (2016) Differential effects of testosterone and estradiol on clitoral function: an experimental study in rats. J. Sex Med. 13, 1858–187110.1016/j.jsxm.2016.10.007 - DOI - PubMed
    1. Wu X., Gu Y. and Li L. (2017) The anti-hyperplasia, anti-oxidative and anti-inflammatory properties of Qing Ye Dan and swertiamarin in testosterone-induced benign prostatic hyperplasia in rats. Toxicol. Lett. 265, 9–1610.1016/j.toxlet.2016.11.011 - DOI - PubMed
    1. Zhang H., Shi L., Ren G.Q.. et al. (2016) Dihydrotestosterone modulates endothelial progenitor cell function via RhoA/ROCK pathway. Am. J. Transl. Res. 8, 4300–4309 - PMC - PubMed
    1. Olsen J.R., Azeem W., Hellem M.R.. et al. (2016) Context dependent regulatory patterns of the androgen receptor and androgen receptor _target genes. BMC Cancer 16, 377.10.1186/s12885-016-2453-4 - DOI - PMC - PubMed

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