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  • The association of male gender with

    2024-02-07

    The association of male gender with increased atherosclerosis has stimulated interest in the role of androgen signalling in this condition. Androgens act (Fig. 2) by direct activation of androgen receptor (AR), a nuclear receptor that acts as a ligand-regulated transcription factor (Gao et al., 2005). AR was cloned in 1988 although its presence was recognised earlier (Lubahn et al., 1988). It has a classic nuclear receptor structure consisting of an N-terminal domain (NTD), DNA-binding domain (DBD), hinge region and ligand-binding domain (LBD) (Fig. 2(Inset)) (Matias et al., 2000). Inactive AR is predominantly localised in NVP-CGM097 but can also be found in the nucleus of some cell types (Jenster et al., 1993). The classical activation pathway (Fig. 2 (Main Figure)) is triggered by LBD-binding of the endogenous ligand (testosterone (T) or dihydrotestosterone (DHT)) which induces a conformational change in AR and dimerization, followed by translocation to the nucleus where the DBD binds specific androgen response elements (ARE) of target genes (Claessens et al., 2001) (one of the target genes activated is the gene for AR) (Chang et al., 1988). Pharmacological agents may induce ligand-specific conformational changes in the receptor to selectively activate specific genes/sets of genes, e.g. by recruitment of different co-regulators (reviewed in Heinlein and Chang, 2002). Non-genomic androgen effects have also been identified involving membrane receptors or interactions of AR with intracellular signalling proteins (Foradori et al., 2008, Toocheck et al., 2016). In addition to direct activation of AR, it is important to note that some effects of testosterone and dehydroepiandrosterone (DHEA; an endogenous metabolic intermediate in androgen and oestrogen biosynthesis, with weak partial agonist activity at AR) may be AR-independent, resulting from conversion of testosterone to oestrogens by the enzyme aromatase (Rahman and Christian, 2007). The influence that conversion of androgen into oestrogens has on atherosclerosis will not be addressed in detail in the article (see Murakami et al., 2001, Jones et al., 2004, Nathan et al., 2001, Villablanca et al., 2004). The first evidence of a role for androgens in regulating cardiovascular disease (Fig. 3) arose from clinical studies in the 1940s (Levine and Likoff, 1943). In brief, these studies demonstrated an association between low endogenous androgens and a high incidence of CHD (Lichtenstein et al., 1987, Hak et al., 2002), as well as increased cardiovascular mortality during androgen deprivation therapy (Zhao et al., 2014). In contrast, high circulating androgen levels have been associated with detrimental effects of androgens on the cardiovascular system in relation to anabolic steroid misuse (Dhar et al., 2005) and during ART in hypogonadal men (Basaria et al., 2010). There are also indications that maintaining testosterone levels in a physiological range using testosterone replacement therapy may be detrimental for CHD as a recent clinical trial demonstrated an increase in coronary plaque volume in aged hypogonadal men receiving topical gel testosterone replacement (Budoff et al., 2017). Detailed discussion of the complex clinical debates involving the interpretation of these data is beyond the scope of this article and is expertly reviewed elsewhere (Kloner et al., 2016). It is clear, however, that the influence of androgens on clinical CV events is complex and remains controversial, and the molecular signalling mechanisms involved require further clarification. In particular, since AR is the dominant mediator of androgens, elucidation of its role in atherosclerosis is key to understanding the role of androgens in the clinical setting.
    Role of AR in models of atherosclerosis Conflicting information derived from clinical studies has highlighted the need for carefully-designed experimental models to help clarify the role of androgens/AR in atherosclerosis. The first direct evidence of a role for androgens in vascular remodelling was reported in the 1970s (Fig. 3) when they were shown to increase the elastin and collagen content of the rat aorta (Wolinsky, 1972). Radioligand binding experiments subsequently demonstrated the presence of AR in canine blood vessels (Horwitz and Horwitz, 1982). This triggered a series of animal studies combining a cholesterol-rich diet with androgen supplementation, with a small number reporting a pro-atherogenic effect (Table 1A(i)) and the majority showing atheroprotection (Table 1A(ii)). It is possible that conflicting results were due to variations in study design, such as: dose selection, differences in lipid profile in different models (e.g. rabbit, mouse) used, different methods for measurement of lesion size, and the use of different androgens (testosterone, DHEA). A timeline summarising the major discoveries regarding the role of AR in atherosclerosis is shown in Fig. 3.