High Affinity NAD+-dependent 11β-hydroxysteroid Dehydrogenase in the Human Heart

doi:10.1006/jmcc.1996.0072

Journal of Molecular and Cellular Cardiology

Volume 28, Issue 4, April 1996, Pages 781-787

https://doi.org/10.1006/jmcc.1996.0072 Get rights and content

Abstract

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 11β-hydroxysteroid dehydrogenase (11β-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 11β-HSD predominates within human heart. Although two 11β-HSD isoforms were detected in human cardiac tissues, the activity of high-affinity (type 2) 11β-HSD was found to be at least twice that of low affinity (type 1) 11β-HSD. Human cardiac type 2 11β-HSD possesses characteristics identical to the high-affinity enzyme of distal renal tubules; 11β-dehydrogenation of corticosterone or cortisol to their 11-keto metabolites is NAD⁺-dependent and, with corticosterone as substrate, the enzyme has a nanomolar K_m(15.1 nmas determined by Lineweaver–Burke analysis). Furthermore, its activity is unidirectional; corticosterone and cortisol are 11β-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 11β-HSD sequence, demonstrated that the high-affinity species of 11β-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 11β-HSD plays an important role in the human heart to promote glucocorticoid metabolism and to confer MC specificity upon MR.

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Citation Excerpt :
Upon adipocyte maturation and expression of H6PD, 11β-HSD1 becomes a reductase [221–223]. 11β-HSD2 is a unidirectional NAD+-dependent dehydrogenase that converts cortisol and corticosterone to the inactive cortisone and 11-dehydrocorticosterone [210,215,224]. Aldosterone is not a substrate.
Mineralocorticoid receptors (MR) mediate diverse functions supporting osmotic and hemodynamic homeostasis, response to injury and inflammation, and neuronal changes required for learning and memory. Inappropriate MR activation in kidneys, heart, vessels, and brain hemodynamic control centers results in cardiovascular and renal pathology and hypertension. MR binds aldosterone, cortisol and corticosterone with similar affinity, while the glucocorticoid receptor (GR) has less affinity for cortisol and corticosterone. As glucocorticoids are more abundant than aldosterone, aldosterone activates MR in cells co-expressing enzymes with 11β-hydroxydehydrogenase activity to inactivate them. MR and GR co-expressed in the same cell interact at the molecular and functional level and these functions may be complementary or opposing depending on the cell type. Thus the balance between MR and GR expression and activation is crucial for normal function. Where 11β-hydroxydehydrogenase 2 (11β-HSD2) that inactivates cortisol and corticosterone in aldosterone target cells of the kidney and nucleus tractus solitarius (NTS) is not expressed, as in most neurons, MR are activated at basal glucocorticoid concentrations, GR at stress concentrations. An exception may be pre-autonomic neurons of the PVN which express MR and 11β-HSD1 in the absence of hexose-6-phosphate dehydrogenase required to generate the requisite cofactor for reductase activity, thus it acts as a dehydrogenase. MR antagonists, valuable adjuncts to the treatment of cardiovascular disease, also inhibit MR in the brain that are crucial for memory formation and exacerbate detrimental effects of excessive GR activation on cognition and mood. 11β-HSD1 inhibitors combat metabolic and cognitive diseases related to glucocorticoid excess, but may exacerbate MR action where 11β-HSD1 acts as a dehydrogenase, while non-selective 11β-HSD1&2 inhibitors cause injurious disruption of MR hemodynamic control. MR functions in the brain are multifaceted and optimal MR:GR activity is crucial. Therefore selectively targeting down-stream effectors of MR specific actions may be a better therapeutic goal.
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Studies in rat vascular endothelial cells, human cardiomyocytes and human vascular smooth muscle cells show expression of 11βHSD2 (Lombes et al., 1995; Slight et al., 1996; Smith et al., 1996; Brem et al., 1998; Hatakeyama et al., 1999; Souness et al., 2002). In contrast to the studies which detected 11βHSD2 in human cardiac myocytes (Lombes et al., 1995; Slight et al., 1996), two other studies (Albiston et al., 1994; Smith & Krozowski, 1996) and all animal studies in Table 1 showed that cardiomyocytes lack 11βHSD2. Under pathological conditions, however, modulation of the expression of 11βHSD1 and −2 in these cell types has been reported.
Despite state-of-the-art reperfusion therapy, morbidity and mortality remain significant in patients with an acute myocardial infarction. Therefore, novel strategies to limit myocardial ischemia–reperfusion injury are urgently needed. Mineralocorticoid receptor (MR) antagonists are attractive candidates for this purpose, since several clinical trials in patients with heart failure have reported a survival benefit with MR antagonist treatment. MRs are expressed by several cells of the cardiovascular system, including cardiomyocytes, cardiac fibroblasts, vascular smooth muscle cells, and endothelial cells. Experiments in animal models of myocardial infarction have demonstrated that acute administration of MR antagonists, either before ischemia or immediately at the moment of coronary reperfusion, limits infarct size. This action appears to be independent of the presence of aldosterone and cortisol, which are the endogenous ligands for the MR. The cardioprotective effect is mediated by a nongenomic intracellular signaling pathway, including adenosine receptor stimulation, and activation of several components of the Reperfusion Injury Salvage Kinase (RISK) pathway. In addition to limiting infarct size, MR antagonists can improve scar healing when administered shortly after reperfusion and can reduce cardiac remodeling post myocardial infarction. Clinical trials are currently being performed studying whether early administration of MR antagonists can indeed improve prognosis in patients with an acute myocardial infarction, independent of the presence of heart failure.
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Citation Excerpt :
In addition to the classic adrenal biosynthetic pathway, steroid hormone production occurs in various other organs, including the brain,23 the vasculature, and the heart.24,25 Angiotensin II is an important regulator of ALDO biosynthesis and secretion in the adrenal cortex, and probably, also in the heart.26-28 In AMI, local tissue angiotensin II production is enhanced, and it is probable that this may be one of the factors leading to increased cardiac ALDO production in AMI.
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Corticosteroids have been shown to play a role in cardiac remodeling, with the possibility of a direct effect of overexpression of 11β-hydroxysteroid dehydrogenase (11HSD) isoform 2 at the level of the cardiomyocytes. The aim of this study was to examine cardiac steroid metabolism in hypertensive rats with hearts that are hypertrophied and fibrotic and have structural alterations in the coronary circulation. To assess possible alterations of cardiac steroid metabolism the expression and activity of both isoforms of 11β-hydroxysteroid dehydrogenase (11HSD) were studied in spontaneously hypertensive rats (SHR), their normotensive controls Wistar–Kyoto (WKY), and in Dahl salt-sensitive (DS) and salt-resistant rats (DR) kept on a low- or high-salt diet. Using real-time quantitative RT-PCR and enzyme activity assay we found strain-dependent differences in cardiac metabolism of glucocorticoids. In Dahl rats expression of 11HSD1 and 11HSD2 mRNA was lower in DS than in DR rats and was not influenced by dietary salt intake; 11HSD1 mRNA was expressed at higher level than 11HSD2 mRNA. NADP⁺-dependent cardiac 11HSD activity showed similar distribution as 11HSD1 mRNA—lower activity in DS than in DR rats and no effect of salt intake. In SHR and WKY strains 11HSD2 mRNA expression was significantly higher in WKY than in SHR but no differences were observed in 11HSD1 mRNA abundance and NADP⁺-dependent 11HSD activity. These results show that the heart is able to metabolize glucocorticoids and that this metabolism is strain-dependent but do not support the notion of association between cardiac hypertrophy and changes of 11HSD1 and 11HSD2 expression.
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^☆: Please address all correspondence to: Simon Slight, University of Missouri-Columbia, Department of Internal Medicine, MA432 Medical Sciences Building, Columbia, MO 65212, U.S.A.

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Regular PaperHigh Affinity NAD+-dependent 11β-hydroxysteroid Dehydrogenase in the Human Heart☆

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High Affinity NAD⁺-dependent 11β-hydroxysteroid Dehydrogenase in the Human Heart☆