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PubMed1994

11 beta-hydroxysteroid dehydrogenase activity in human lung cells and transcription regulation by glucocorticoids.

Selectivity to aldosterone (Aldo) in mineralocorticoid target tissues has been suggested to be due to the activity of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD). This enzyme inactivates the endogenous glucocorticoid cortisol, thus permitting the unhindered access of Aldo to the mineralocorticoid receptor. The 11 beta-HSD activity was measured by the conversion of cortisol to cortisone and vice versa. Concomitant treatment of the cells with either cortisone or cortisol in the presence of the glycyrrhetinic acid derivative carbenoxolone (CBX) blocked both activities of 11 beta-HSD. Dexamethasone and Aldo activated the transcription of transiently transfected mouse mammary tumor virus-bacterial chloramphenicol acetyltransferase chimeric gene in LU-19 cells. The transcription activation by cortisol was synergized by concomitant treatment of the transfectants with CBX. Transactivation with Aldo was inhibited by spironolactone. The enzyme 11 beta-HSD in LU-19 cells is similar to the cloned liver isoform and catalyzes both reduction and dehydrogenation.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1996

11 beta-hydroxysteroid dehydrogenase modulation of glucocorticoid activities in lymphoid organs.

The immunoregulatory effects of glucocorticoids (GCS) are linked to their capacity to alter the production of various species of cytokines associated with immune and inflammatory processes. The present study determined that the influences of GCS within particular lymphoid organs vary, depending on the specific activity of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) within the tissue. This enzyme converts active GCS to inactive metabolites and was found to display greater activity in peripheral than in mucosal lymphoid organs. A direct correlation was found between 11 beta-HSD activity and the preferential production of type 1 cytokines by T-cells residing within certain lymphoid organs. It was established that lymphoid organ 11 beta-HSD was localized in the immobile stromal cell components. Inhibition of 11 beta-HSD activity in vivo reduced type 1 and enhanced type 2 cytokine production by activated T-cells, and it also depressed the ability of animals to generate contact hypersensitivity responses. We conclude that GCS levels can be controlled within lymphoid organs through oxidative inactivation by 11 beta-HSD. GCS action is, therefore, dependent on tissue levels of 11 beta-HSD activity, the number of GCS receptors in a responsive cell, and the concentration of circulating GCS.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2003

Stimulation of 11-beta-hydroxysteroid dehydrogenase type 2 in rat colon but not in kidney by low dietary NaCl intake.

Data suggest that mineralocorticoid selectivity is differentially regulated in epithelial target tissues. We investigated whether the level of dietary NaCl intake influenced the expression and tissue distribution of 11-beta-hydroxysteroid dehydrogenase type 2 (11betaHSD-2), aldosterone receptor (MR), and glucocorticoid receptor (GR) in rat colon, kidney, and cardiovascular tissue. Rats were fed a diet with 0.01 or 3% NaCl for 10 days. Messenger RNAs were analyzed with ribonuclease protection assay, 11betaHSD-2 protein by Western blot analysis, and localization of GR and 11betaHSD-2 by immunohistochemistry. NaCl restriction elevated plasma renin and aldosterone concentration, whereas corticosterone was unaltered. In distal colon, 11betaHSD-2 mRNA and protein were augmented significantly by low-NaCl intake and immunolabeling was widely distributed in crypt and surface epithelium. The MR mRNA level was decreased, whereas GR mRNA was unaltered in distal colon. MR, GR, and 11betaHSD-2 mRNAs were not changed in kidney cortex and medulla, left cardiac ventricle, and aorta. Immunofluorescence labeling showed that GR and 11betaHSD-2 localization was mutually exclusive in kidney. In colon epithelium, nuclear staining for GR subsided as perinuclear 11betaHSD-2 immunoreactivity increased with NaCl restriction. As a functional correlate of increased 11betaHSD-2 expression in colon, the GR-stimulated sodium-hydrogen exchanger NHE-3 was lowered by NaCl restriction. Inhibition of 11betaHSD-2 activity by carbenoxolone during NaCl restriction stimulated NHE-3 expression in colon. Dexamethasone stimulated NHE-3 both in colon and kidney. These data indicate that mineralocorticoid selectivity is physiologically regulated by NaCl intake at the level of 11betaHSD-2 expression and tissue distribution in the distal colon, but not in the kidney.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗
PubMed1991

11 beta-Hydroxysteroid dehydrogenase mRNA expression in rat kidney.

11 beta-Hydroxysteroid dehydrogenase (11 beta-OHSD) protects nonspecific renal mineralocorticoid receptors from exposure to circulating glucocorticoid in vivo by catalyzing the conversion of corticosterone to inactive 11-dehydrocorticosterone. Although 11 beta-OHSD bioactivity and aldosterone binding sites are found in distal tubular cells, mineralocorticoid receptor and 11 beta-OHSD immunoreactivities are not colocalized. However, there are several kidney isoforms of 11 beta-OHSD, not all of which may be immunoreactive, whereas only a single mRNA species has been described. Using in situ hybridization we found 11 beta-OHSD mRNA is highly expressed in all renal tubular epithelia in the rat. It is therefore likely that 11 beta-OHSD is colocalized with mineralocorticoid receptors in distal tubular cells.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1993

Activity of 11 beta-hydroxysteroid dehydrogenase in toad bladder: effects of 11-dehydrocorticosterone.

11 beta-Hydroxysteroid dehydrogenase (11 beta-OHSD) transforms circulating glucocorticoids to their "biologically inert" 11-dehydro derivatives. Isoforms of 11 beta-OHSD with different cofactor requirements and biochemical properties [Michaelis constant (Km) and maximal velocity (Vmax)] exist in the kidney. Since epithelial cells derived from the toad bladder also contain this enzyme, we wished to further characterize its properties in prepared cell homogenates. 11 beta-OHSD from toad bladder demonstrated a clear preference for NAD+ over NADP+ as a cofactor similar to that observed in renal cortical collecting duct (CCD) cells. Furthermore, 11 beta-OHSD had a rapid onset of action. The apparent Km for corticosterone was 16.3 x 10(-8) M, a value comparable to that observed for enzyme from CCD, and a Vmax of 4.8 x 10(-12) mol.mg protein-1.min-1. The end product, 11-dehydrocorticosterone (compound A), influenced enzyme activity; it increased 11 beta-OHSD activity at corticosterone concentrations below the apparent Km for the enzyme and inhibited 11 beta-OHSD activity at corticosterone concentrations above the Km for the enzyme. The inhibitory effects of compound A appeared noncompetitive with an apparent equilibrium constant (Ki) of 2.8 x 10(-7) M. Consistent with its inhibitory action on 11 beta-OHSD, compound A (10(-6) M) enhanced the short-circuit current response to corticosterone (10(-7) M) in the intact toad bladder (experimental 2.03 +/- 0.33 vs. control 1.40 +/- 0.17 times above baseline; n = 7, P < 0.01). Thus 11 beta-OHSD in toad bladder resembles the isoform found in CCD, and compound A may be biologically important as a regulator of 11 beta-OHSD.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1993

Expression and characterization of a new species of 11 beta-hydroxysteroid dehydrogenase in Xenopus oocytes.

11 beta-Hydroxysteroid dehydrogenase (11-OHSD) plays a critical role in conferring aldosterone specificity to mineralocorticoid target cells. We have recently described a novel isoform of 11-OHSD in the collecting duct (11-OHSD/CD), which differs from the previously characterized isoform (11-OHSD-1) in kinetic parameters, cofactor dependency, and reversibility of the reaction. Unlike 11-OHSD-1, the collecting duct enzyme catalyzes irreversible dehydrogenation of endogenous glucocorticoids, has a very high affinity for its substrate, and is located in mineralocorticoid target cells; it thus appears well suited to "protect" the mineralocorticoid receptors from occupancy by glucocorticoids. As a first step in attempting to isolate the cDNA for the 11-OHSD/CD isoform, we isolated mRNA from immunodissected cortical collecting duct (CCD) cells and characterized the 11-OHSD in oocytes injected with this mRNA. Water-injected oocytes had no measurable 11-OHSD activity. In contrast, oocytes injected with as little as 1 ng CCD mRNA expressed detectable 11-OHSD activity. Expression of 11-OHSD activity was dependent on the amount of mRNA injected and was maximal with 30 ng mRNA. Similar to the findings in CCD cells, the expressed enzyme preferred NAD over NADP (activity was 0.46 +/- 0.04 and 0.011 +/- 0.01 fmol.min-1.oocyte-1 with 0.1 mM NAD and NADP, respectively). The Michaelis constant (Km) for corticosterone was 11.5 +/- 3.7 nM. Similar to the findings in CCD cells, the expressed enzyme worked predominantly in the oxidative direction, as back-conversion of [3H]dehydrocorticosterone to corticosterone was negligible. (ABSTRACT TRUNCATED AT 250 WORDS)

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2001

Distal tubular electrolyte transport during inhibition of renal 11beta-hydroxysteroid dehydrogenase.

To test the proposal that the enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD) confers aldosterone specificity on mineralocorticoid receptors in the distal nephron by inactivating glucocorticoids, we performed a free-flow micropuncture study of distal tubular function in adrenalectomized rats infused with high-dose corticosterone. One-half of the rats were additionally given intravenous carbenoxolone (CBX; 6 mg/h) to inhibit renal 11beta-HSD activity. Although this maneuver lowered fractional Na(+) excretion (1.1 +/- 0.2 vs. 1.9 +/- 0.2%, P < 0.01), Na(+) reabsorption within the accessible distal tubule was found to be similar in the two groups of animals. In contrast, distal tubular K(+) secretion was enhanced in CBX-treated rats: fractional K(+) deliveries to the early and late distal collection sites in the corticosterone-alone group were 13 +/- 1 and 20 +/- 3%, respectively (not significant), whereas corresponding data in the CBX-treated group were 9 +/- 1 and 24 +/- 2% (P < 0.01). This stimulation of distal K(+) secretion provides the first direct in vivo evidence that 11beta-HSD normally prevents corticosterone from exerting a mineralocorticoid-like effect in the distal tubule. The reduction in fractional Na(+) excretion during inhibition of 11beta-HSD, in the absence of a change in end-distal Na(+) delivery, suggests enhanced Na(+) reabsorption in the collecting ducts.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2005

Selective insensitivity of ZR-75-1 human breast cancer cells to 2-methoxyestradiol: evidence for type II 17beta-hydroxysteroid dehydrogenase as the underlying cause.

2-Methoxyestradiol (2-MeO-E2), a nonpolar endogenous metabolite of 17beta-estradiol, has strong antiproliferative, apoptotic, and antiangiogenic actions. Among the four human breast cancer cell lines tested (MCF-7, T-47D, ZR-75-1, and MDA-MB-435s), the ZR-75-1 cells were selectively insensitive to the antiproliferative actions of 2-MeO-E2, although these cells had a similar sensitivity as other cell lines to several other anticancer agents (5-fluorouracil, mitomycin C, doxorubicin, colchicine, vinorelbine, and paclitaxel). Mechanistically, this insensitivity is largely attributable to the presence of high levels of a steroid-selective metabolizing enzyme, the type II 17beta-hydroxysteroid dehydrogenase (17beta-HSD), in the ZR-75-1 cells, which rapidly converts 2-MeO-E2 to the inactive 2-methoxyestrone, but this enzyme does not metabolically inactivate other nonsteroidal anticancer agents. The type II 17beta-HSD-mediated conversion of 2-MeO-E2 to 2-methoxyestrone in ZR-75-1 cells followed the first-order kinetics, with a very short half-life (approximately 2 hours). In comparison, the T-47D, MCF-7, and MDA-MB-435s human breast cancer cells, which were highly sensitive to 2-MeO-E2, had very low or undetectable catalytic activity for the conversion of 2-MeO-E2 to 2-methoxyestrone. Reverse transcription-PCR analysis of the mRNA levels of three known oxidative 17beta-HSD isozymes (types II, IV, and VIII) revealed that only the type II isozyme was selectively expressed in the ZR-75-1 cells, whereas the other two isozymes were expressed in all four cell lines. Taken together, our results showed, for the first time, that the high levels of type II 17beta-HSD present in ZR-75-1 cells were largely responsible for the facile conversion of 2-MeO-E2 to 2-methoxyestrone and also for the selective insensitivity to the antiproliferative actions of 2-MeO-E2.

17-Hydroxysteroid Dehydrogenases↗
PubMedDate not supplied

Effects of changes in dietary intake of sodium and potassium and of metabolic acidosis on 11beta-hydroxysteroid dehydrogenase activities in rat kidney.

BACKGROUND/AIM: Glucocorticoid activity is modulated by NADP(+)- and NAD(+)-dependent isoforms of the enzyme 11beta-hydroxysteroid dehydrogenase (11betaHSD) which convert glucocorticoids to their inactive metabolites. The NAD(+)-dependent isoform, 11betaHSD2, is present in the distal nephron where it confers aldosterone specificity on mineralocorticoid receptors. The objective of this study was to establish whether renal 11betaHSD activities are affected by changes in sodium and potassium balance and by metabolic acidosis. METHODS: Renal 11betaHSD activities were measured ex vivo from rats fed normal and high- and low-potassium diets and a low-sodium diet or given 1.5% NH(4)Cl to drink. RESULTS: Rats maintained on high-potassium and low-sodium diets exhibited 59% (p < 0.01) and 28% (p < 0.05) decreases, respectively, in NAD(+)-dependent renal 11betaHSD activity (relative to rats fed control diet) with no changes in NADP(+)-dependent cortisol oxidation. Short-term (3 day) and longer-term (10 day) metabolic acidosis also decreased NAD(+)-dependent 11betaHSD activity by 50 and 52%, respectively, without affecting NADP(+)-dependent cortisol oxidation. The low-potassium diet had no detectable effect on renal 11betaHSD activities. CONCLUSION: These results suggest that adaptations to a high-potassium or a low-sodium diet and to metabolic acidosis involve decreases in renal 11betaHSD2 activity, enhancing the access of glucocorticoids to renal corticosteroid receptors.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1999

In vivo characterization of 11beta-hydroxysteroid dehydrogenase in rat hippocampus using glucocorticoid neuroendangerment as an endpoint.

11beta-Hydroxysteroid dehydrogenase (11beta-HSD) is the enzyme responsible for the interconversion of corticosterone (CORT) to 11-dehydrocorticosterone (11-DHC). CORT is an adrenal hormone secreted during the stress response and it has widespread effects in many different target tissues. In addition, CORT can exacerbate damage caused by neurological insults, such as kainic acid-induced seizures. In addition to its protective role in the kidney, 11beta-HSD is also thought to play a role in steroid regulation in the brain. However, it is not known whether the enzyme is acting in vivo as a reductase or a dehydrogenase. If the enzyme is working as a reductase, converting 11-DHC to CORT, it has the potential to exacerbate neurotoxicity due to other agents. On the other hand, 11beta-HSD could be neuroprotective if the enzyme is acting as a dehydrogenase, deactivating CORT by converting it into 11-DHC. To characterize the enzyme in vivo, we have utilized glucocorticoid neuroendangerment in the hippocampus as an indirect assay of 11beta-HSD function. We have shown that 11-DHC can exacerbate kainic acid toxicity in adrenalectomized (ADX) rats and this exacerbation is blocked by the 11beta-HSD antagonist, carbenoxolone; these findings suggest that 11beta-HSD is working as a reductase in ADX rats. The presumptive reductase activity found in ADX rats was derived from both hippocampal and peripheral forms of the enzyme. In the presence of physiological levels of glucocorticoids, reductase activity was decreased and no dehydrogenase activity was detected. The present study demonstrates that 11beta-HSD reductase activity, both in vivo and in vitro, occurs only in the presence of low levels of circulating glucocorticoids.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1995

Localization of the gene for human 11 beta-hydroxysteroid dehydrogenase type 2 (HSD11B2) to chromosome band 16q22.

The enzyme 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta HSD2) is an NAD-dependent, high-affinity isoform that potently inactivates glucocorticoids. In the present study we have used fluorescence in situ hybridization and an 11 beta HSD2 cDNA isolated from human kidney as probe to localize the gene encoding 11 beta HSD2. The gene, which has been given the symbol HSD11B2, maps to human chromosome band 16q22.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMedDate not supplied

Immunohistochemical localization of 11-hydroxysteroid dehydrogenase in rat kidney with monoclonal antibody.

Monoclonal antibody (MAb) against 11-hydroxysteroid dehydrogenase (11-HSD) has been raised by immunization of female balb/c mice. 11-HSD from solubilized rat renal microsomal protein could be bound in a modified ELISA using antimouse IgG and MAb against 11-HSD. On Western blots of solubilized rat renal microsomes the MAb recognized a single protein band of an approximate molecular weight of 35 kD. Immunohistochemical staining of rat renal tissue with the above MAb and the APAAP staining technique displayed a heterogenous reginal and subcellular distribution: glomeruli and arterioles were practically devoid of specific staining, as were epithelial cells in inner and outer medulla. Intense immunostaining was observed in PCT and particularly in PST, appearing granular with highest density around the nuclei. Here the enzyme bound to intracellular membranes may exert an autocrine function such as signal inactivation. In contrast to cortex, staining of interstitial cells was observed in renal medulla. The latter localization is compatible with the concept of a paracrine function of 11-HSD which might prevent corticosterone from gaining access to collecting duct cells.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMedDate not supplied

Corticosterone increases Na(+)-K(+)-ATPase activity in rat cortical collecting ducts with inhibition of 11 beta-hydroxysteroid dehydrogenase.

To examine a physiological role of 11 beta-hydroxysteroid dehydrogenase (11OHSD) in the aldosterone target tissue, we measured Na(+)-K(+)-ATPase activity in the cortical collecting ducts (CCD) from adrenalectomized rats, which were treated with a physiological dose of corticosterone and/or carbenoxolone (an inhibitor of 11OHSD). The Na(+)-K(+)-ATPase activity in adrenalectomized rats was not significantly changed by either corticosterone alone or carbenoxolone alone, whereas its activity showed a significant increase only in the rats that received both corticosterone and carbenoxolone. In these rats, the plasma concentration of corticosterone was within the physiological range (10(-6) M) and the plasma carbenoxolone concentration was about 10(-7) M. Furthermore, the direct effect of carbenoxolone was examined in the microdissected CCD because it has been reported that carbenoxolone per se had an affinity for the aldosterone receptor. Na+K(+)-ATPase activity in the microdissected CCD was increased in a dose-dependent manner after a 3-hour incubation with carbenoxolone, and this effect was completely inhibited by canrenoic acid (an aldosterone antagonist). However, the minimal carbenoxolone concentration exerting a stimulatory effect was 10(-6) M, which is about 10 times higher than the plasma concentration of carbenoxolone in the in vivo treated rats. These results indicate that an inhibition of 11OHSD but not a direct action of carbenoxolone induces an increase in Na(+)-K(+)-ATPase activity, which is a well-known aldosterone effect in the CCD.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1990

Renal 11-beta-hydroxysteroid dehydrogenase: a mechanism ensuring mineralocorticoid specificity.

In vitro studies with mineralocorticoid receptors (MR) have shown that they are non-specific and do not distinguish between glucocorticoids (cortisol in man, corticosterone in rodents) and aldosterone. These findings contrast with in vivo aldosterone selectivity. Our studies on the congenital deficiency of the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD; which converts cortisol to cortisone or corticosterone to 11-dehydrocorticosterone) and acquired deficiency secondary to liquorice or carbenoxolone indicate that this enzyme plays a crucial role in protecting the MR from glucocorticoid exposure. The localisation of 11 beta-OHSD in both the proximal and distal nephron suggests that it has both an autocrine and a paracrine role. The presence of this protective mechanism in the toad bladder suggests that it is at least 300 million years old.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1995

Alcohol inhibits 11-beta-hydroxysteroid dehydrogenase activity in rat kidney and liver.

Male Wistar rats were treated with different ethanol concentrations diluted in drinking water in order to evaluate the effect of acute ethanol intoxication on 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) activity in liver and kidney tissue homogenates. Rats with the highest ethanol consumption (15% ethanol supplementation) showed a significant decrease in both hepatic and renal 11 beta-OHSD activity as compared to the control group (p < 0.005). In the same group, aldosterone plasma levels were significantly lower than in controls (p < 0.01), while corticosterone (B) plasma levels were slightly higher, suggesting that the increase in intrarenal B concentrations, probably related to the acute ethanol consumption, might be responsible for a nonspecific B mineralocorticoid activity.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1993

11-beta-Hydroxysteroid dehydrogenase of rat lung: enzyme kinetic, oxidase-reductase ratio, electrolyte and trace element dependence.

The modulation of the intracellular glucocorticoidal effect on surfactant synthesis of the fetal lung by the metabolic capacity of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) could be an important factor in lung maturation. The kinetic properties of microsomal 11 beta-HSD of the rat lung are characterized with respect to product inhibition, substrate specificity, effect of electrolytes or trace elements, and the dependence of the oxidase reductase (OR) ratio on incubation conditions. With NADP+ product inhibition of the reductase was demonstrated. The most common trace elements and electrolytes exhibited no effect on the activity of 11 beta-HSD. It is shown that the OR ratio was strongly dependent on assay conditions. With optimal assay conditions oxidase activity exceeds reductase activity in adult and fetal rat lung microsomes (OR ratio > 1). Thus, glucocorticoids are mainly metabolized to their inactive forms. The enzyme activity in the adult is about 10 times higher than in the fetal lung. The low enzyme activity in fetal lungs could be the reason why the glucocorticoidal effects on surfactant synthesis are not suppressed despite the predominance of oxidase activity.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2001

Endothelin 1 type a receptor antagonism prevents vascular dysfunction and hypertension induced by 11beta-hydroxysteroid dehydrogenase inhibition: role of nitric oxide.

BACKGROUND: The enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD) prevents inappropriate activation of the nonselective mineralocorticoid receptors by glucocorticoids. Renal activity of 11beta-HSD is decreased in patients with apparent mineralocorticoid excess (SAME), licorice-induced hypertension, and essential hypertension. Although expressed in vascular cells, the role of 11beta-HSD in the regulation of vascular tone remains to be determined. METHODS AND RESULTS: lycyrrhizic acid (GA; 50 mg/kg IP, twice daily for 7 days) caused a significant inhibition of 11beta-HSD activity and induced hypertension in Wistar-Kyoto rats (157 versus 127 mm Hg in controls; P<0.01). After 11beta-HSD inhibition, aortic endothelial nitric oxide (NO) synthase (eNOS) protein content, nitrate tissue levels, and acetylcholine-induced release of NO were blunted (all P<0.05 versus controls). In contrast, vascular prepro-endothelin (ET)-1 gene expression, ET-1 protein levels, and vascular reactivity to ET-1 were enhanced by GA treatment (P<0.05 versus controls). Chronic ET(A) receptor blockade with LU135252 (50 mg. kg(-1). d(-1)) normalized blood pressure, ET-1 tissue content, vascular reactivity to ET-1, vascular eNOS protein content, and nitrate tissue levels and improved NO-mediated endothelial function in GA-treated rats (P<0.05 to 0.01 versus untreated and verapamil-treated controls). In human endothelial cells, GA increased production of ET-1 in the presence of corticosterone, which indicates that activation of the vascular ET-1 system by 11beta-HSD inhibition can occur independently of changes in blood pressure but is dependent on the presence of glucocorticoids. CONCLUSIONS: Chronic ET(A) receptor blockade normalizes blood pressure, prevents upregulation of vascular ET-1, and improves endothelial dysfunction in 11beta-HSD inhibitor-induced hypertension and may emerge as a novel therapeutic approach in cardiovascular disease associated with reduced 11beta-HSD activity.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1995

Prerequisite for cardiac aldosterone action. Mineralocorticoid receptor and 11 beta-hydroxysteroid dehydrogenase in the human heart.

BACKGROUND: It has been proposed that aldosterone exerts direct effects on heart function, most notably on the development of myocardial fibrosis during ventricular hypertrophy in rat. Initial events in aldosterone action entail its binding to mineralocorticoid receptor (MR). Because MR displays similar affinities for aldosterone and glucocorticoids, the in vivo aldosterone selectivity of MR requires the presence of an enzyme, 11 beta-hydroxysteroid dehydrogenase (11-HSD), which metabolizes glucocorticoids into inactive derivatives. Although evidence exists for the presence of MR in rodent heart, no data are available for humans; moreover, the existence of cardiac 11-HSD is controversial. METHODS AND RESULTS: The heart samples used originated from tissue removed during cardiac surgery in nontransplant patients or from endocavitary biopsies done for the follow-up of heart transplantation. The expression of MR was examined at the mRNA and protein level by in situ hybridization with cRNA probes specific for human MR mRNA and by immunodetection with two specific anti-MR antibodies. 11-HSD catalytic activity was determined by measurement of the metabolic rate of tritiated corticosteroids by cardiac samples. In nontransplanted hearts, an in situ hybridization signal equivalent to that found in the whole kidney was present on cardiomyocytes. Specific immunolabeling of cardiomyocytes with anti-MR antibodies demonstrated the presence of the MR protein. Cardiac 11-HSD activity was detected (243 +/- 26 fmol.30 min-1.mg protein-1) and was dependent on the cofactor NAD, not NADP, suggesting that it corresponds to the form of the enzyme specifically responsible for MR protection. In transplanted hearts that presented severe alterations, MR immunodetection was weaker and irregular, with no specific hybridization signal. CONCLUSIONS: Our results demonstrate that MR is coexpressed with 11-HSD in human heart, which thus possesses the cellular machinery required for direct aldosterone action.

11-beta-Hydroxysteroid Dehydrogenases↗