Dehydroepiandrosterone, the Endothelium, and Cardiovascular Protection

Dehydroepiandrosterone (DHEA) sulfate (DHEAS) is the most abundant circulating steroid hormone in humans (1). Although there are wide variations, the plasma concentrations of DHEA and DHEAS progressively decline with age (2, 3, 4), suggesting that they may be implicated in the aging process, and perhaps in cardiovascular aging, on which has been built a case for DHEA supplementation in aging individuals. Over the past 10 yr, preparations of DHEA have been available over the counter and on the internet and have been sold as the “fountain of youth.” This has raised concerns about the possible effects of such uncontrolled and widespread hormonal self-administration and the lack of quality control in this increasingly rewarding business. Although DHEA replacement may seem an attractive theoretical concept, there are very few definitive reports on the biological functions of this steroid, and it is still the case that its regulation is unclear and its mechanisms of action largely yet to be established. In this issue of Endocrinology, Liu et al. (5) make an important contribution to this area, on the molecular actions of DHEA. Based on a variety of approaches, Liu et al. elegantly show that DHEA acts as a survival factor for vascular endothelial cells. This observation is a point of departure for some of the reported beneficial actions of DHEA on the vascular system and may provide a rationale for the epidemiological linkage of DHEA and cardiovascular disease. Several epidemiological studies have shown an inverse correlation between DHEA/DHEAS plasma concentrations and mortality, particularly mortality due to cardiovascular disease. The Rancho Bernardo study was the first to correlate DHEAS levels with cardiovascular risk in males over 50 yr of age (6). Subsequently, a number of studies have extended this observation to young men (7) as well as to premenopausal (8) and postmenopausal women (9). Low DHEAS levels have been also associated with cardiovascular events (10), with the extent of angiographic coronary stenosis (11), as well as with allograft vasculopathy (12), suggesting a role for DHEAS in delaying coronary disease. Not all the studies are concordant in showing a cardioprotective action of DHEA. For example, the later reanalysis of the Rancho Bernardo cohort showed a much weaker correlation between the peripheral levels of the steroid and coronary heart disease (13). However, relatively recent evidence from the prospective PAQUID study has renewed interest in this issue, again showing higher mortality in male patients correlated with lower DHEAS concentrations (14, 15). These clinical findings are supported by animal studies that indicate a protective role of DHEA against atherosclerotic disease in primates (16) and rabbits (17, 18), although the identification of the mechanisms involved is still work in progress. The great conundrum in this area is the lack of a clear mechanism of action of DHEA. It is known that this steroid serves as a precursor for estrogens and androgens, and many believe that DHEA is merely an inactive precursor pool for the formation of bioactive steroid hormones. To this extent, oral supplementation of DHEA in postmenopausal women results in the formation of significant amounts of 17β-estradiol and estrone, accompanied by increases of androstenedione, testosterone, and dihydrotestosterone (19). This, plus the evidence that DHEA can also be converted into estrogens and other androgens within cells (20), supports the view that many actions of this steroid are indirect and mediated via estrogen and/or androgen receptors. This may also be true for blood vessels, as shown by a report indicating that the reduction of atherosclerotic lesions by DHEA in rabbits is in part mediated by conversion to estrogens (21). There is, however, increasing evidence for DHEA acting in its own right through a dedicated, although as yet unidentified, receptor. The existence of such a receptor for DHEA has been particularly investigated in vascular cells, where DHEA binds with high affinity to the endothelial cell membrane, and is not displaced by structurally related steroids (22). Binding of DHEA to the cell membrane is coupled to recruitment of G proteins such as Gαi2 and Gαi3 that mediate the rapid activation of intracellular signaling cascades (22) (Fig. 1⇓). Our own data support these results of rapid recruitment of G proteins at the cell membrane and later recruitment of ERK 1/2 MAPK when DHEA is added to human endothelial cells in vitro (23) (Fig. 1⇓). These effects are not prevented by the blockade of androgen or estrogen receptors, and DHEA signals via the endothelial nitric oxide synthase, which is rapidly recruited to increase synthesis of nitric oxide, a powerful vasodilator and antiinflammatory agent (23) (Fig. 1⇓). The induction of nitric oxide synthesis by DHEA is thus highly relevant for vascular function and may provide a mechanistic explanation for the antiatherogenic effects of this steroid in animals (21) and in humans, as well as for its antiinflammatory (12) effects. The present report by Liu et al. further extends the biological reach of this steroid and shows that part of its alleged antiaging actions in vessels may reflect a reduction of programmed cell death in the endothelium. This action of DHEA requires recruitment of a cell membrane G protein of the Gαi family and is independent of the conversion of DHEA to estrogens and the estrogen receptor. The other remarkable observation in the paper by Liu et al. is that DHEA triggers a rapid recruitment of the phosphatidylinositol 3 OH kinase/Akt pathway, which mediates the antiapoptosis action of DHEA (Fig. 1⇓). Recruitment of this pathway is a common feature of different steroid receptors (24), including the estrogen receptor α (24, 26), the progesterone receptor (27), and the glucocorticoid receptor (28). This suggests that this particular action might be a basic and necessary function of nuclear receptors that has been conserved throughout evolution. If this is true, it might also suggest that the yet-uncharacterized receptor for DHEA might belong to this large family of receptors, although evidence for additional family members is lacking. Alternatively, it may be truly a membrane-located seven-transmembrane G protein-coupled receptor, which constitutes a much larger receptor family. In conclusion, although there is still debate on DHEA, there is already compelling evidence that this steroid is not just an inactive side product of the adrenals, but rather a hormone in its own right, and that it modulates a series of processes in the body. Only future research will tell whether this steroid is or is not implicated in the aging process or in vascular degeneration. Even in the evidence-based third millennium, the dream of a natural fountain of youth is an enticing one for which answers are likely to come over the next decade