Converting enzymes implications for genomic and nongenomic effects

In various cells of the vascular wall, testosterone can exert direct effects either by activation of the androgen receptor or by non-genomic effects on plasma membrane receptors and channels (see Chapters 1 and 2). Thus testosterone can modulate calcium fluxes by mechanisms that are independent of androgen and estrogen receptors in macrophages and endothelial cells. (Benten et al. 1999; Guo et al. 2002; Lieberherr and Grosse 1994; Rubio-Gayosso et al. 2002). This could account for the effects of supraphysiological dosages of testosterone on vasoreac-tivity which are not inhibited by antagonists of the androgen and estrogen receptors in contrast to some effects seen with physiological dosages (reviewed in Liu etal. 2003; Wu and von Eckardstein 2003). There is also evidence that testosterone regulates macrophage function by non-genomic effects via a G-protein-coupled, agonist-sequestrable plasma membrane receptor which initiates calcium- and 1,4,5-trisphosphate-signaling pathways (Lieberherr and Grosse 1994).

The androgen receptor has been found to be expressed in endothelial cells, smooth muscle cells, macrophages, platelets and cardiomyocytes, all of which are relevant to atherosclerosis and heart failure. (reviewed in Hayward etal. 2000; Liu etal. 2003; Wu and von Eckardstein 2003). Expression of the androgen receptor in human arterial endothelial and smooth muscle cells has not been shown directly, although the association of endothelium-dependent and - independent vasoreac-tivity with the CAG repeat polymorphism in the androgen receptor provides some indirect evidence in support (Zitzmann et al. 2001b). It is also important to note that in several vascular cells, androgen receptor expression was higher if they were derived from male rather than female donors (Hanke et al. 2001; Higashiura et al. 1997; McCrohon et al. 2000). In addition, the expression of aromatase in smooth muscle cells, endothelial cells and macrophages opens the possibility of local conversion of testosterone into estradiol (Diano et al. 1999; Harada et al. 1999). Both the classic estrogen receptor ERa and the alternative estrogen receptor ERß are expressed by various vascular cells, so that testosterone can also modulate vascular physiology indirectly via local estradiol production (Hayward et al. 2000; Ho and Liao 2002; Hodges etal. 2000; Rubanyi etal. 1997).

Cardiomyocytes express both androgen and estrogen receptors as well as aromatase and 5a-reductase. (Marsh etal. 1998; Thum and Borlak 2002; Weinberg etal. 1999) so that testosterone may regulate cardiomyocyte growth and function either directly through the androgen receptor or indirectly via the estrogen receptor.

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