Introduction The burden of cardiovascular disease CVD is

Introduction The burden of cardiovascular disease (CVD) is undisputed, accounting for approximately a third of global deaths (17.5 million people in 2012) (WHO, 2012). Atherosclerosis leads to the development of coronary heart disease (CHD) which accounts for more than 40% of these deaths (WHO, 2012). Rupture of atherosclerotic plaques may lead to thrombotic events, such as stroke and myocardial infarction, which, if not fatal, cause significant morbidity. The influence of sex hormones on CVD is not entirely clear. Men are at considerably higher risk of developing CVD compared with age-matched women (Huang et al., 2016), suggesting gender plays a role in this risk, possibly through protective effects of oestrogens, detrimental effects of androgens (Liu et al., 2003, Dixit et al., 2015), or both. This contrasts with studies suggesting that reduced androgen levels are associated with increased risk of CHD in men (Wu and Von Eckardstein, 2003); this has particular relevance to the use of androgen deprivation therapy in men with prostatic cancer (Martin-Merino et al., 2011, Zareba et al., 2016). Retrospective observational studies have triggered numerous prospective clinical studies (Liu et al., 2003, Dixit et al., 2015), as well as pre-clinical studies in experimental animals (Malkin et al., 2003), designed to clarify the impact of androgens and the androgen receptor (AR) in atherosclerosis. Despite this continuing work, the use of androgen replacement therapy (ART) in men with androgen deficiency, and androgen deprivation therapy in prostate cancer, continues to rise worldwide (Baillargeon et al., 2013, Gan et al., 2013) without a clear understanding of the influence of AR stimulation on the development and progression of atherosclerosis. This gap in our understanding of the relationship between androgens and atherogenesis has major implications for society, as a public health issue, and for individual men with, and at risk of, CVD. Specifically, there is a need to clarify the impact of age-related decline in androgen levels on cardiovascular disease in men and develop therapeutic strategies that harness the benefits of ART while avoiding the short and longer term CV risks. Clarifying the role of androgen receptor-mediated responses in cells of the Aprepitant will be important in the development of targeted selective androgen receptor modulating drugs (SARMs) (Clarke and Khosla, 2009).
Atherosclerosis and androgen receptor – where do they meet? Atherosclerosis has a venerable pedigree, with evidence of the disease in pre-industrial populations. The 5300 year old mummy of Otzi the iceman was shown to have extensive atherosclerotic lesions (Keller et al., 2012). Similarly, remarkable studies of more than 100 mummies, of individuals spanning a period of 4000 years and representing 4 regionally-distinct early populations, identified atheromatous lesions throughout the vasculature of one third of the bodies examined: suggesting that humans are inherently predisposed to atherosclerosis (Thompson et al., 2013), although recent evidence suggests that it can be completely avoided in certain environmental conditions (Kaplan et al., 2017). Atherosclerosis is an inflammatory disease of the vascular wall attributed to a response-to-injury stimulated by chronic accumulation of lipid (Fig. 1): a process exacerbated by the modern-day high-calorie diet and a sedentary life-style. It is a progressive condition, involving components of all layers of the arterial wall (Libby and Hansson, 2015) initiated by endothelial cell dysfunction under the influence of altered blood flow and exposure to cardiovascular risk factors (Ross, 1999). This stimulates expression of adhesion molecules (such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) (Hansson, 2005)) on endothelial cells, combined with the production of chemoattractants such as monocyte chemoattractant protein-1 (MCP-1) (Smith et al., 1995). These changes promote attachment, and subsequent transmigration into the intima, of immune cells. Macrophages recruited in this way phagocytose oxidised low-density lipoprotein (ox-LDL) particles and become foam cells, contributing to the formation of fatty streaks (the characteristic early lesion of atherosclerosis) (Stary et al., 1994). Subsequent secretion of proliferative factors induces vascular smooth muscle cell (VSMC) proliferation contributing to atheromatous plaque growth with formation of an overlying fibrous cap (Newby and Zaltsman, 1999). Vascular remodelling is also associated with neovascularisation within the lesion, which may further facilitate cell infiltration, resulting in destabilisation of the atheromatous plaque (Moulton, 2006, Camare et al., 2017). Eventually, progressive VSMC death and secretion of proteases in the plaque increases the likelihood of rupture which in turn can result in thrombotic occlusion of the entire blood vessel (Falk et al., 1995).