11β-Hydroxysteroid Dehydrogenase in Cultured Human Vascular Cells

Abstract

Abstract-11␤-Hydroxysteroid dehydrogenases (11␤-HSD) interconvert cortisol, the physiological glucocorticoid, and its inactive metabolite cortisone in humans. The diminished dehydrogenase activity (cortisol to cortisone) has been demonstrated in patients with essential hypertension and in resistance vessels of genetically hypertensive rats. 11␤-Hydroxysteroid dehydrogenase type 2 (11␤-HSD2) catalyzes only 11␤-dehydrogenation. However, a functional relationship between diminished vascular 11␤-HSD2 activity and elevated blood pressure has been unclear. In this study we showed the expression and enzyme activity of 11␤-HSD2 and 11␤-HSD type 1 (which is mainly oxoreductase, converting cortisone to cortisol) in human vascular smooth muscle cells. Glucocorticoids and mineralocorticoids increase vascular tone by upregulating the receptors of pressor hormones such as angiotensin II. We found that physiological concentrations of cortisol-induced increase in angiotensin II binding were significantly enhanced by the inhibition of 11␤-HSD2 activity with an antisense DNA complementary to 11␤-HSD2 mRNA, and the enhancement was partially but significantly abolished by a selective aldosterone receptor antagonist. This may indicate that impaired 11␤-HSD2 activity in vascular wall results in increased vascular tone by the contribution of cortisol, which acts as a mineralocorticoid. In congenital 11␤-HSD deficiency and after administration of 11␤-HSD inhibitors, suppression of 11␤-HSD2 activity in the kidney has been believed to cause renal mineralocorticoid excess, resulting in sodium retention and hypertension. In the present study we provide evidence for a mechanism that could link impaired vascular 11␤-HSD2 activity, increased vascular tone, and elevated blood pressure without invoking renal sodium retention.

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.…”

“…First, the precise cellular distribution of 11HSD isozymes in the vessel wall is uncertain. 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.…”

Fluid Shear Stress Reduces 11β-Hydroxysteroid Dehydrogenase Type 2

“…RT of 1 g total RNA in the presence of oligo(dT) [12][13][14][15][16][17][18] primer and 200 U Moloney murine leukemia virusreverse transcriptase (both GIBCO BRL) was followed by PCR performed in a Perkin-Elmer ABI Prism 7700 Thermal Cycler Sequence Detection System with ABI Prism PrimerExpress Software. The 11␤-HSD2 PCR product was normalized by the GAPDH PCR product.…”

“…7,8 An increased cortisol availability within the vascular wall, a known target for glucocorticoids and mineralocorticoids, could be essential for the response to vasoactive mediators, such as the pressor hormones angiotensin II (Ang II) and ␣-adrenergic agonists. 9 Glucocorticoids, such as dexamethasone, have been shown (1) to stimulate Ang II type 1A (AT 1A ) receptor expression via glucocorticoid responsive elements in the gene promotor, 10,11 (2) to enhance AT 1 receptor binding of Ang II in vascular smooth muscle cells, 12 and (3) to reduce AT 2 receptor expression, 13 all of which could also explain the sensitization to Ang II in PE.…”

Subjects with essential hypertension are more sensitive to the inhibition of 11 β-HSD by liquorice

“…3,14,15 The role of 11 b-HSD in HT is complex, since the enzyme has been found in the human heart as well as in blood vessels of both man and rat. [16][17][18][19] Cortisolinduced dermal vasoconstriction is increased in humans with inhibited or a defect 11 b-HSD activity, 20 and after topical application of cortisol, the dermal vasoconstriction has been shown to be increased in patients with HT compared to controls, indicating a decreased 11 b-HSD activity. This suggestion is supported by the finding of a prolonged half-life of cortisol in patients with HT.…”