Intra-vascular glucocorticoid metabolism as a modulator of vascular structure and function

Abstract

The ability of glucocorticoids to directly alter arterial function, structure and the inflammatory response to vascular injury may contribute to their well-established link with the development of cardiovascular disease. Recent studies have emphasised the importance of tissue-specific regulation of glucocorticoid availability by the 11 beta-hydroxysteroid dehydrogenase (11HSD) isozymes, which inter-convert active glucocorticoids and their inactive metabolites. The expression of both type 1 and type 2 11HSDs in the arterial wall suggests that prereceptor metabolism of glucocorticoids may have a direct impact on vascular physiology. Indeed there is evidence that 11HSDs influence glucocorticoid-mediated changes in vascular contractility, vascular structure, the inflammatory response to injury and the growth of new blood vessels. Hence, inhibition of 11HSD isozymes may provide a novel therapeutic target in vascular disease.

Acute In Vivo Regulation of 11β-Hydroxysteroid Dehydrogenase Type 1 Activity by Insulin and Intralipid Infusions in Humans

“…The insertion of the microdialysis cannulae causes significant local trauma so that it is possible that this reflects 11HSD1 favoring dehydrogenase activity only when it is dissociated from H6PDH in damaged tissues. 11HSD type 2 in the local vasculature may contribute to dehydrogenase activity (34). Notably, the dehydrogenase activity was of smaller magnitude than reductase activity in adipose tissue, consistent with previous arteriovenous sampling studies demonstrating net cortisone extraction from sc adipose (35).…”

Impaired Protein Stability of 11β-Hydroxysteroid Dehydrogenase Type 2

“…We reinvestigated the steroid hormone metabolites both in plasma and in dialysate (Table 1). Because the kidney is the main site of 11␤-HSD2 expression, total body 11␤-HSD2 activity is reduced in hemodialysis patients (14,15) and remaining activity may originate mainly from colon and vascular endothelial cells (20). In this patient, cortisol concentrations in plasma and dialysate were in the same range as those in patients who were on hemodialysis (14,15).…”

Obesity and corticosteroids: 11β-Hydroxysteroid type 1 as a cause and therapeutic target in metabolic disease

“…Both 11 -HSD1 and 11 -HSD2 appear to be expressed in human endothelial cells, and modulate inducible nitric oxide synthase (iNOS) activity (Liu et al, 2008). The story in rodents is less clear, but suggests that expression of 11 -HSD isoforms may be both species and anatomical (perhaps fat depot) site-specific (Hadoke et al, 2006). 11 -HSD1 is expressed in smooth muscle cells (Hadoke et al, 2006), and as described below, in macropahges.…”

“…The story in rodents is less clear, but suggests that expression of 11 -HSD isoforms may be both species and anatomical (perhaps fat depot) site-specific (Hadoke et al, 2006). 11 -HSD1 is expressed in smooth muscle cells (Hadoke et al, 2006), and as described below, in macropahges. All three cell Page 14 of 31 A c c e p t e d M a n u s c r i p t 15 types are critical for the formation of atherosclerotic plaques.…”