Therapeutic manipulation of glucocorticoid metabolism in cardiovascular disease

Abstract

The therapeutic potential for manipulation of glucocorticoid metabolism in cardiovascular disease was revolutionized by the recognition that access of glucocorticoids to their receptors is regulated in a tissue-specific manner by the isozymes of 11beta-hydroxysteroid dehydrogenase. Selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 have been shown recently to ameliorate cardiovascular risk factors and inhibit the development of atherosclerosis. This article addresses the possibility that inhibition of 11beta-hydroxsteroid dehydrogenase type 1 activity in cells of the cardiovascular system contributes to this beneficial action. The link between glucocorticoids and cardiovascular disease is complex as glucocorticoid excess is linked with increased cardiovascular events but glucocorticoid administration can reduce atherogenesis and restenosis in animal models. There is considerable evidence that glucocorticoids can interact directly with cells of the cardiovascular system to alter their function and structure and the inflammatory response to injury. These actions may be regulated by glucocorticoid and/or mineralocorticoid receptors but are also dependent on the 11beta-hydroxysteroid dehydrogenases which may be expressed in cardiac, vascular (endothelial, smooth muscle) and inflammatory (macrophages, neutrophils) cells. The activity of 11beta-hydroxysteroid dehydrogenases in these cells is dependent upon differentiation state, the action of pro-inflammaotory cytokines and the influence of endogenous inhibitors (oxysterols, bile acids). Further investigations are required to clarify the link between glucocorticoid excess and cardiovascular events and to determine the mechanism through which glucocorticoid treatment inhibits atherosclerosis/restenosis. This will provide greater insights into the potential benefit of selective 11beta-hydroxysteroid dehydrogenase inhibitors in treatment of cardiovascular disease.

Figure 1

Strategies for pharmacological manipulation of glucocorticoid activity. (A) Therapeutic manipulation of glucocorticoid generation and action. Synthesis of active glucocorticoids (predominantly cortisol in man and corticosterone in rodents) can be targeted by inhibiting key enzymes in the pathway. Action of glucocorticoids on corticosteroid receptors can be blocked using selective antagonists of glucocorticoid (GR) and mineralocorticoid (MR) receptors. (B) Manipulation of glucocorticoid metabolism. Glucocorticoid generation in target tissues can be targeted using inhibitors of 11β-hydroxysteroid dehydrogenase (11-HSD) which interconverts active steroid and its inert 11-keto metabolite. Clearance of glucocorticoids by 5α-reductase is also inhibited by compounds used to inhibit conversion of testosterone into dihydrotestosterone.

Figure 2

Systemic vs. local effects of glucocorticoids on the cardiovascular system. Systemic actions of glucocorticoids are associated with increased cardiovascular risk and are likely to promote cardiovascular disease development. Local effects on cells of the cardiovascular system may be mediated by glucocorticoid (GR) and/or mineralocorticoid (MR) receptors and could be predicted either to promote or oppose lesion development.

Figure 3

The influence of inflammation on 11β-hydroxysteroid dehydrogenase activity in murine arteries. Glucocorticoid generation in (A) isolated mouse aorta and femoral artery and (B) perfused mouse hindlimb is catalysed exclusively by 11-HSD1 type 1 as deletion of this isozyme completely prevents generation of corticosterone. Exposure of mice to a pro-inflammatory stimulus [lipopolysaccharide (LPS), 6 h] produced a small increase in reductase activity that achieved significance in isolated arteries (C) but not in the perfused hindlimb (D). Similarly, induction of an inflammatory response to intravascular injury in the mouse femoral artery (E) did not increase 11-HSD1 reductase activity in either the presence or absence of pro-inflammatory cytokines (Interleukin 1β; IL-1β) in vitro. Adapted with permission from Dover et al., 2007Endocrinology, 148, 166–172.