histamine-1 receptor antagonist br AR mediated actions in ce

AR-mediated actions in histamine-1 receptor antagonist of the vascular wall Sex hormones may influence the size and composition of atherosclerotic lesions indirectly by modifying systemic cardiovascular risk factors such as plasma lipids profiles and insulin sensitivity; this aspect of their action is discussed elsewhere (Jones and Saad, 2009). In order to completely understand the role of AR in atherosclerosis, the specific influence of androgens on the cells involved in lesion formation need to be clarified.
Conclusion and future perspectives In summary, although the majority of results from animal models suggest an atheroprotective role for androgens, the influence of AR activation on atherosclerosis remains unclear. Furthermore, the importance of dose, duration of exposure and source (endogenous or pharmacological) has not been determined. Differences in study design (including the difficulties with restoration of physiological androgen levels in castrated animals, variations in methods used to generate lesions and measure lesion size, site-, gender- and model-specific effects) often make direct comparisons difficult. Direct evidence for AR-mediated actions on atherosclerosis is scarce with AR-mutant and global-ARKO models being used only recently. These models provide useful insights but some have cardiovascular characteristics (e.g. plasma lipid anomalies, vascular dysfunction) and low androgen levels that may confound interpretation of results. In vitro studies in ECs and VSMCs have produced conflicting data (showing variously that stimulation of AR is pro- or anti-atherogenic) and are not always consistent with results obtained from in vivo investigations. This is exemplified by the most recent findings in (immune and vascular) cell-specific ARKO mice. Future work in vascular remodelling may make use of inducible ARKO models, along with investigation of cell-specific deletions (which retain normal circulating testosterone concentrations), to shed more light on the role of AR and the significance of their tissue distribution. Selective ARKO in other vascular (e.g. pericytes, adventitial cells) or extra-vascular cells (De Gendt et al., 2004) may aid in deciphering the importance of AR. The use of synthetic AR agonists with better selectivity for, and potency at, AR may prove useful in confirming the influence of these receptors on atherosclerosis. Defining the role of AR signalling in atherosclerosis could identify novel therapeutic options in CHD. In particular, improving our understanding of the cells in the cardiovascular system that are influenced by androgen receptor agonists will help develop SARMs that have a beneficial effect on cardiovascular health. However, a key issue may be determining the optimum therapeutic dose or plasma level of androgen to minimise adverse cardiovascular risk while harnessing optimal beneficial effects. An intriguing future approach that requires much more work would be to use SARMs to target AR in a tissue/cell specific manner (e.g. selective targeting of macrophages). Improving our understanding of the cells in the cardiovascular system that are influenced by androgen receptor agonists will help develop SARMs that have a beneficial effect on cardiovascular health. It is clear, however, that significantly more research is needed to enable us to understand the role of androgen-mediated stimulation of AR in atherosclerosis and the implications of this interaction for patients with heart disease or for those requiring androgen replacement or androgen deprivation therapy.
Funding Funded by a British Heart Foundation Project Grant award to LBS, PWFH, and MAD (PG/11/72/29334), an MRC Programme Grant award to LBS (MR/N002970/1), and the BHF Centre for Research Excellence.
Conflict of interest
Jun Luo had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.