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.

Decreased OxLDL uptake and cholesterol efflux in THP1 cells elicited by cortisol and by cortisone through 11β-hydroxysteroid dehydrogenase type 1

“…One way Anova significancy and Bonferroni post Test analysis are included in the graph: *p < 0.05 vs without OxLDL or AcLDL; þ p < 0.05 vs with OxLDL or AcLDL; A p < 0.05 vs OxLDL plus cortisol and C p < 0.05 vs with OxLDL plus cortisona. activity, and it has been reported that 11bHSD1 deficiency/inhibition in the organism is atheroprotective whereas 11bHSD2 deficiency/inhibition accelerates atherosclerosis [45]. However, 11bHSD1 and 11bHSD2 expression in macrophages, and their contribution to the development of foam cells and progression of atherosclerosis, remain unclear.…”

The Multifaceted Mineralocorticoid Receptor

“…This increase is adaptive in acute injury or stress, however increased 11β-HSD1 and glucocorticoid action due to the chronic inflammation in cardiometabolic syndrome or diabetes leads to inappropriate MR and GR activation (69, 70). It has been proposed that structural damage and remodeling of vessels associated with age, is caused by a relative increase in 11β-HSD1 over 11β-HSD2 activity, allowing cortisol to activate the MR, as well as the GR, upsetting the normal MR:GR activation ratio (200,221). Limited early trials with selective 11β-HSD1 antagonists improved glycemic control in obese type 2 diabetics (20, 219, 466).…”

Blood pressure and amiloride-sensitive sodium channels in vascular and renal cells

“…Furthermore, endothelial cells express mineralocorticoid receptors, 134–136 as well as 11-βHSD2, which confers mineralocorticoid specificity, 137 although the relative activity of 11-βHSD2 at the local tissue level in vascular cells is an important issue that needs to be further developed. 138 Endothelial expression and membrane insertion of EnNaCs is enhanced by aldosterone. 139–141 Amiloride is associated with inactivation of EnNaC activity at the cell surface.…”