Modulation of 11β-hydroxysteroid dehydrogenase as a strategy to reduce vascular inflammation

Abstract

Atherosclerosis is a chronic inflammatory disease in which initial vascular damage leads to extensive macrophage and lymphocyte infiltration. Although acutely glucocorticoids suppress inflammation, chronic glucocorticoid excess worsens atherosclerosis, possibly by exacerbating systemic cardiovascular risk factors. However, glucocorticoid action within the lesion may reduce neointimal proliferation and inflammation. Glucocorticoid levels within cells do not necessarily reflect circulating levels due to pre-receptor metabolism by 11β-hydroxysteroid dehydrogenases (11β-HSDs). 11β-HSD2 converts active glucocorticoids into inert 11-keto forms. 11β-HSD1 catalyses the reverse reaction, regenerating active glucocorticoids. 11β-HSD2-deficiency/inhibition causes hypertension, whereas deficiency/inhibition of 11β-HSD1 generates a cardioprotective lipid profile and improves glycemic control. Importantly, 11β-HSD1-deficiency/inhibition is atheroprotective, whereas 11β-HSD2-deficiency accelerates atherosclerosis. These effects are largely independent of systemic risk factors, reflecting modulation of glucocorticoid action and inflammation within the vasculature. Here, we consider whether evidence linking the 11β-HSDs to vascular inflammation suggests these isozymes are potential therapeutic targets in vascular injury and atherosclerosis.

Fig 1

Regulation of 11β-hydroxysteroid dehydrogenase isozyme activity in health and disease. (a) The biochemical pathways that regulate 11β-HSDs. A number of factors have been identified that selectively increase (green arrows) or decrease (red lines) 11β-HSD isozyme expression [–109]. Note: only some of the biochemical pathways that regulate 11β-HSD expression are shown; factors that may affect 11β-HSD activity (eg. glucose-6-phosphate availability, hexose-6-phosphate dehydrogenase activity [110] and insulin signaling) are not shown. Little is known about the pathways that regulate 11β-HSD2 activity in the vasculature. (b) The relationship between 11β-HSD isozyme activity and disease pathologies. High (top left) and low (bottom left) activity of 11β-HSD1, and low activity of 11β-HSD2 (top right) are all associated with disease pathologies