High affinity NAD(+)-dependent 11 beta-hydroxysteroid dehydrogenase in the human heart.
Receptor-ligand binding is an essential component of mineralocorticoid (MC) activity in target tissues. Detection of type 1 mineralocorticoid receptors (MR) in cardiac tissue is therefore suggestive that, like kidney, the heart is MC responsive. The presence of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) within MC responsive tissue is essential to prevent saturation of MR by glucocorticoids. Using both high-performance liquid chromatography (HPLC) and thin layer chromatography (TLC), we have found that a high-affinity species of 11 beta-HSD predominates within human heart. Although two 11 beta-HSD isoforms were detected in human cardiac tissues, the activity of high-affinity (type 2) 11 beta-HSD was found to be at least twice that of low affinity (type 1) 11 beta-HSD. Human cardiac type 2 11 beta-HSD possesses characteristics identical to the high-affinity enzyme of distal renal tubules; 11 beta-dehydrogenation of corticosterone or cortisol to their 11-keto metabolites is NAD(+)-dependent and, with corticosterone as substrate, the enzyme has a nanomolar Km (15.1 nM as determined by Lineweaver-Burke analysis). Furthermore, its activity is unidirectional; corticosterone and cortisol are 11 beta-dehydrogenated to inactive 11-keto metabolites, whereas 11-oxoreductase activity (conversion of 11-dehydrocorticosterone and cortisone to corticosterone and cortisol, respectively) is absent. RT/PCR analysis, using primers complementary to the human renal type 2 11 beta-HSD sequence, demonstrated that the high-affinity species of 11 beta-HSD expressed in human heart is indeed the same enzyme as that produced in the kidney. These findings strongly suggest that, as is the case in the distal portion of the nephron, type 2 11 beta-HSD plays an important role in the human heart to promote glucocorticoid metabolism and to confer MC specificity upon MR.
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Department of Internal Medicine, University of Missouri Health Sciences Center, Columbia, USA.
Ganjam
V K
VK
Gómez-Sánchez
C E
CE
Zhou
M Y
MY
Weber
K T
KT
D001483:Base Sequence; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D005938:Glucocorticoids / Q000378:metabolism; D016027:Heart Transplantation; D006801:Humans; D008969:Molecular Sequence Data; D009206:Myocardium / Q000166:cytology / Q000201:enzymology*; D009252:NADPH Dehydrogenase / Q000302:isolation & purification / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011987:Receptors, Steroid / Q000378:metabolism
D005938:Glucocorticoids; D011987:Receptors, Steroid; D009252:NADPH Dehydrogenase