1lβ-Hydroxysteroid Dehydrogenase in Vascular Smooth Muscle and Heart: Implications for Cardiovascular Responses to Glucocorticoids*

Abstract

The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) converts the active glucocorticoid corticosterone to inactive 11-dehydrocorticosterone in the rat (or cortisol to cortisone in man), thereby protecting renal mineralocorticoid receptors from corticosterone or cortisol and allowing preferential access for aldosterone. We have previously demonstrated that cortisol-induced cutaneous vasoconstriction in man is potentiated by the 11 beta-OHSD inhibitor glycyrrhetinic acid, suggesting that 11 beta-OHSD may protect vascular corticosteroid receptors. In this study we report quantitation of 11 beta-OHSD bioactivity in homogenates of rat aorta, mesenteric artery, caudal artery, and heart, expressed as the percent in vitro conversion of 3H-corticosterone to 3H-11-dehydrocorticosterone. Nicotinamide adenine dinucleotide phosphate (NADP+)-dependent 11 beta-OHSD activity was found in all of these tissues and was significantly higher in resistance vessels than aorta (P less than 0.05) [without NADP+: caudal artery (4.2 +/- 0.2%) greater than mesenteric artery (2.5 +/- 0.7%) = heart (1.67 +/- 0.2%) greater than aorta (0.79 +/- 0.2%); with 200 microM NADP+: caudal artery (43.9 +/- 2.1%) greater than heart (20.6 +/- 1.0%) = mesenteric artery (17.7 +/- 3.1%) = aorta (11.4 +/- 0.4%); heart greater than aorta]. All of these were lower than renal cortex (29.4 +/- 1.8% without NADP+; 82.4 +/- 0.4% with NADP+; P less than 0.001). 3H-11-dehydrocorticosterone was the major metabolite of 3H-corticosterone (greater than 97% of 3H-corticosterone metabolized). Reduction of 3H-11-dehydrocorticosterone to 3H-corticosterone was not detected in these experiments. We also report localization of 11 beta-OHSD-like immunoreactivity by immunohistochemistry using antisera raised against rat liver 11 beta-OHSD, and of 11 beta-OHSD messenger RNA expression by in situ hybridization using complementary RNA probes transcribed from complementary DNA encoding rat liver 11 beta-OHSD. We found 11 beta-OHSD immunoreactivity and messenger RNA expression in vascular and cardiac smooth muscle cytoplasm but not in endothelium. Thus, 11 beta-OHSD is appropriately sited to modulate access of corticosterone to vascular receptors and could influence vascular resistance, cardiac output and thereby blood pressure.

11β-Hydroxysteroid Dehydrogenase Type 2 in Mouse Aorta

“…11 Isolation of the medial layer of the aorta from the endothelium (confirmed by the absence of TIE-2 mRNA expression) allowed the demonstration that 11HSD1 but not 11HSD2 mRNA is expressed in the smooth muscle cells. This is consistent with histological studies 15 and studies in vascular smooth muscle cells cultured from rat aorta 12 but contrasts with the detection of both 11HSD1 and 11HSD2 mRNA expression in vascular smooth muscle cells cultured from human coronary arteries 13 and aorta. 14 These differences may reflect the use of smooth muscle from different species and different vascular territories but may also be due to changes in 11HSD isozyme expression resulting from the use of cultured cells.…”

“…In cells in primary culture, 11HSD1 and 11HSD2 have been detected in vascular smooth muscle cells, [12][13][14] adventitial fibroblasts, and endothelial cells. 12 However, histological studies in rat vessels suggest that immunoreactivity for 11HSD1 is restricted to vascular smooth muscle 15,16 ; data for 11HSD2 are inconsistent, probably on account of the varied characteristics of different antisera. 16,17 The inconsistencies in 11HSD isozyme localization in the literature may also be due to differences in expression in arteries from distinct anatomical sites, differences between species, and the use of cultured cells.…”

Glucocorticoids and Cardiovascular Disease

“…GRs are also present in inflammatory cells, which invade vascular lesions, notably in macrophages (66). We have described 11b-HSD1 in vascular smooth muscle and 11b-HSD2 in the endothelium (67,68), although this distribution may vary somewhat between species and between vascular sites ((69, 70), reviewed in (16)). Low levels of 11b-HSD1 and 11b-HSD2 have also been reported in rat and human heart (67,(71)(72)(73)(74)(75) and 11b-HSD1 is expressed in differentiated macrophages (76,77).…”

“…We have described 11b-HSD1 in vascular smooth muscle and 11b-HSD2 in the endothelium (67,68), although this distribution may vary somewhat between species and between vascular sites ((69, 70), reviewed in (16)). Low levels of 11b-HSD1 and 11b-HSD2 have also been reported in rat and human heart (67,(71)(72)(73)(74)(75) and 11b-HSD1 is expressed in differentiated macrophages (76,77). On the balance of the evidence, with reference to the model in There have also been sporadic reports that vascular tissue and myocardium express the enzymes necessary for de novo steroidogenesis from cholesterol (72,78,79), although the magnitude, if any, of this contribution appears to be very small.…”

11β-Hydroxysteroid Dehydrogenase and Corticosteroid Action in Lyon Hypertensive Rats

“…12 The functional significance of 11␤-HSD activity in vascular tissues is interesting. A bidirectional 11␤-HSD1 appears to be expressed in vascular smooth muscle, 7,22 whereas 11␤-HSD1 and 11␤-HSD2 are expressed in vascular endothelial cells. 23 Glucocorticoids are known to control vascular reactivity, 24 and there are reports that inhibition of dehydrogenase activity potentiates the effects of corticosterone on noradrenaline-induced vasoconstriction in aortic rings.…”