Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The syndrome of apparent mineralocorticoid excess (AME) is a heritable form of hypertension due to an inborn error of cortisol metabolism and is characterized by hypokalemia and low renin levels despite subnormal or normal levels of aldosterone and other known mineralocorticoids. The syndrome is attributable to congenital deficiency of the enzyme 11 beta-hydroxydehydrogenase (11 beta-HSD), which converts cortisol (F) to biologically inactive cortisone. This results in a prolonged half-life of F, which acts at the kidney level as a potent mineralocorticoid (MC). In fact, both F and aldosterone have similar affinities in vitro for type I MC receptor (MR), and 11 beta-HSD activity protects the MR in vivo from the higher circulating levels of F. The biochemical marker of this disorder is an increased ratio of tetrahydrocortisol (THF) + allo-THF/tetrahydrocortisone (THE) in the urine, which has been found in more than 20 patients described to date, together with evidence of a more general defect in steroid ring A reduction. Only a few cases (the so-called type II form) described in Italy differ from the classic form having a normal THF/THE ratio, but in both forms the ratio of free urinary F/E has recently been found to be similarly high. Dexamethasone is the treatment of choice but is often inadequate in long term control of high blood pressure. Acquired forms of AME are those consequent on abuse of licorice or carbenoxolone, which both inhibit 11 beta-HSD; the latter also inhibits the reverse 11-oxoreductase reaction leading to somewhat different abnormalities of urinary cortisol/cortisone. So far, two isoenzymes of 11 beta-HSD have been purified and cloned; 11 beta-HSD type 1 is NADP-dependent, abundant in liver, lung, and testis, and catalyzes both 11 beta-dehydrogenation and 11 beta-oxoreduction; no mutation in its gene was detected in patients with AME. A second NAD-dependent isoenzyme is present in kidney and placenta and catalyzes dehydrogenation only. Very recently (1995) two groups have independently demonstrated the presence of mutations in its gene, located in chromosome 16q22. New and co-workers found a point mutation in exon 6 of two affected siblings of an Iranian family, while White and co-workers in parallel studies showed point mutations or small deletions in both alleles in nine unrelated patients; importantly, expression studies showed minimal or absent activity for almost all the mutant sequences. No definite mutations have been so far identified in patients with AME type II. AME is thus the third single gene cause of human hypertension to be described, after glucocorticoid remediable aldosteronism in 1992 and Liddle's syndrome in 1994.
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PMID:Apparent mineralocorticoid excess: type I and type II. 873 99

Recent studies have demonstrated that the interconversion of active and inactive glucocorticoids plays a key role in determining the specificity of the mineralocorticoid receptor and controlling local tissue glucocorticoid receptor activation. Two distinct isoforms of the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) have been identified. 11 beta-HSD1 is NADPH-dependent and at its major site of action (the liver) is a reductase, converting cortisone to cortisol (11-dehydrocorticosterone to corticosterone in the rat). 11 beta-HSD2 is NAD-dependent, is present in tissues such as the kidney and placenta, and converts cortisol to cortisone (corticosterone to 11-dehydrocorticosterone in the rat). Congenital or acquired deficiency of 11 beta-HSD2 produces the syndrome of apparent mineralocorticoid excess (SAME) in which cortisol gains access to the unprotected nonspecific mineralocorticoid receptor. The congenital deficiency is associated with mutations in the gene encoding the kidney isoform of 11 beta-HSD2; the acquired form results from inhibition of the enzyme by licorice, carbenoxolone, ACTH-dependent steroids in the ectopic ACTH syndrome, and possibly circulating inhibitors of the enzyme. This paper focuses on recent evidence, which suggest that low levels of placental 11 beta-HSD2 result in increased exposure of the fetus to maternal glucocorticoid and low birth weight. In animal studies using the rat we have shown that birth weight is correlated positively and placental weight negatively with the level of placental 11 beta-HSD. Thus animals with low birth weight and large placentae were those likely to be exposed to the highest level of maternal glucocorticoid. In man a similar relationship was found with birth weight being significantly correlated either with placental 11 beta-HSD activity or with the extent of cortisol inactivation by isolated perfused placental cotyledons. Administration of dexamethasone (which is poorly metabolized by placental 11 beta-HSD2) to pregnant rats resulted in decreased birth weight and the development of hypertension in the pups when adult. The same results were obtained when pregnant rats were given carbenoxolone, an inhibitor of placental 11 beta-HSD2. Low protein diet during pregnancy in the rat resulted in low birth weight of the pups, increased placental weight but decreased placental 11 beta-HSD activity, and adult hypertension. Thus increased glucocorticoid exposure of the fetus secondary to a failure of the normal inactivation of maternal glucocorticoid by the placental may be an important mechanism linking changes in the in utero environment and common adult diseases.
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PMID:11 beta-Hydroxysteroid dehydrogenases: key enzymes in determining tissue-specific glucocorticoid effects. 873 12

1. The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) converts glucocorticoids to their inactive 11-keto metabolites. The ubiquitous expression of the NADP-dependent isoform (11 beta HSD1) suggest an important role in modulating glucocorticoid action, but little is known about 11 beta HSD1 gene expression and enzymatic activity in the rat heart. 2. In the present study rat cardiac 11 beta HSD1 activity and ontogeny of gene expression have been characterized. The addition of NADP, but not NAD, to heart homogenates resulted in significant increases in the metabolism of both corticosterone and cortisol, with the former substrate displaying far greater metabolism. Both 11 beta HSD1 gene expression and enzyme activity increased in parallel from low levels at 1 week of age to maximal levels at 8 weeks, with no further change by 16 weeks of age. 3. We also compared the activity of 11 beta HSD1 in the hearts of male and female spontaneously hypertensive rats (SHR) with normotensive Wistar-Kyoto (WKY) controls. Enzyme activity in the pooled atria of female SHR was significantly higher than in male SHR atria (7.6 +/- 0.6% conversion of corticosterone vs 4.5 +/- 0.5%; P < 0.05). The left ventricles of female WKY rats contained significantly less 11 beta HSD activity than either male WKY rats or female SHR (8.6 +/- 0.8% conversion vs 17 +/- 1.4 and 13.6 +/- 0.5%, respectively; P < 0.05). In the right ventricle, female WKY rats also had significantly less enzyme activity than either female SHR or male WKY rats (4.9 +/- 0.7 vs 10.0 +/- 1.7 and 10.2 +/- 1.4%; P < 0.05). 4. These results clearly show that the rat heart contains significant amounts of the 11 beta HSD1 enzyme and that this activity is sexually dimorphic. Furthermore, significant differences were observed between a normotensive and hypertensive strain of rat. The relevance of these observations to the aetiology and maintenance of hypertension remains to be explored.
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PMID:11 beta-Hydroxysteroid dehydrogenase type I enzyme in the hearts of normotensive and spontaneously hypertensive rats. 888 82

11 beta-HSD catalyses the interconversion of active and inactive corticosteroids and exists as two isoforms with less than 30% amino acid homology. The bi-directional NADP-dependent type 1 enzyme appears to function as a tissue-specific glucocorticoid provider. The uni-directional NAD-dependent type 2 enzyme functions as a tissue-specific glucocorticoid protector. The syndrome of AME is caused by mutations in the gene of 11 beta-HSD2. Placental 11 beta-HSD2 is a barrier to growth-retarding maternal glucocorticoids and may play a key role in prenatal programming of hypertension.
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PMID:11 beta-Hydroxysteroid dehydrogenases: tissue-specific dictators of glucocorticoid action. 907 55

We have recently demonstrated in a rat model that traumatic brain injury induces perturbation of cellular calcium homeostasis with an overload of cytosolic calcium and excessive calcium adsorbed on the mitochondrial membrane, consequently the mitochondrial respiratory chain-linked oxidative phosphorylation was impaired. We report the effect of a selective N-type calcium channel blocker, SNX-111 on mitochondrial dysfunction induced by a controlled cortical impact. Intravenous administration of SNX-111 at varying times post injury was made. The concentration titration profile revealed SNX-111 at 4 mg kg-1 to be optimal, and the time window to be administration at 4 h post-injury, in line with that reported on the effect of SNX-111 in experimental stroke. Under optimal conditions, SNX-111 significantly improved the mitochondrial respiratory chain-linked functions, such as the electron transfer activities with both succinate and NAD-linked substrates, and the accompanied energy coupling capacities measured as respiratory control indices (RCI) and ATP synthesis (P/O ratio), and the energy linked Ca2+ transport. In order to assess the applicability of these data to the clinical setting, we have initiated studies with brain tissue which has to be resected during surgical treatment. Five patients suffered from brain trauma, one from intracranial hypertension due to stroke (noninfarcted tissue was taken), and one from epilepsy. Our data revealed that brain mitochondria derived from the patient with intracranial hypertension and the patient with epilepsy were tightly coupled with good respiratory rates with glutamate and malate as substrates, and high P/O ratios. The rates of respiration and ATP synthesis were severely impaired in the brain mitochondria isolated from traumatized patients. These results indicate that investigation of brain mitochondrial functions can be used as a measure for trauma-induced impairment of brain energy metabolism. The time window for the effect of SNX-111 in mitochondrial function and the (preliminary) similarity between mitochondrial dysfunction in experimental animals and humans make the drug appear to be well suited for clinical trials in severe head injury.
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PMID:Mitochondrial dysfunction after experimental and human brain injury and its possible reversal with a selective N-type calcium channel antagonist (SNX-111). 919 88

In mammalian tissues, at least two isozymes of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) catalyze the interconversion of hormonally active C11-hydroxylated corticosteroids (cortisol, corticosterone) and their inactive C11-keto metabolites (cortisone, 11-dehydrocorticosterone). The type 1 and type 2 11 beta-HSD isozymes share only 14% homology and are separate gene products with different physiological roles, regulation, and tissue distribution. 11 beta-HSD2 is a high affinity NAD-dependent dehydrogenase that protects the mineralocorticoid receptor from glucocorticoid excess; mutations in the HSD11B2 gene explain an inherited form of hypertension, the syndrome of apparent mineralocorticoid excess in which cortisol acts as a potent mineralocorticoid. By contrast, 11 beta-HSD1 acts predominantly as a reductase in vivo, facilitating glucocorticoid hormone action in key target tissues such as liver and adipose tissue. Over the 10 years, 11 beta-HSD has progressed from an enzyme merely involved in the peripheral metabolism of cortisol to a crucial pre-receptor signaling pathway in the analysis of corticosteroid hormone action. This review details the enzymology, molecular biology, distribution, regulation, and function of the 11 beta-HSD isozymes and highlights the clinical consequences of altered enzyme expression.
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PMID:11 beta-Hydroxysteroid dehydrogenase. 1023 52

Reactive oxygen species have emerged as important molecules in cardiovascular function. Recent work has shown that NAD(P)H oxidases are major sources of superoxide in vascular cells and myocytes. The biochemical characterization, activation paradigms, structure, and function of this enzyme are now partly understood. Vascular NAD(P)H oxidases share some, but not all, characteristics of the neutrophil enzyme. In response to growth factors and cytokines, they produce superoxide, which is metabolized to hydrogen peroxide, and both of these reactive oxygen species serve as second messengers to activate multiple intracellular signaling pathways. The vascular NAD(P)H oxidases have been found to be essential in the physiological response of vascular cells, including growth, migration, and modification of the extracellular matrix. They have also been linked to hypertension and to pathological states associated with uncontrolled growth and inflammation, such as atherosclerosis.
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PMID:NAD(P)H oxidase: role in cardiovascular biology and disease. 1072 Apr 9

The role of the enzyme 11beta-hydroxysteroid dehydrogenase (11betaHSD) in hypertension remains unknown even if it appears that the inappropriately decreased 11betaHSD activity might be involved in a process that leads to high blood pressure. The possible changes of 11betaHSD were therefore investigated in rats with spontaneous or salt-induced hypertension. The adult male rats of the following genotypes were used: spontaneously hypertensive rats (SHR), normotensive Wistar-Kyoto rats (WKY), Dahl salt-sensitive rats fed either a high-salt diet containing 8% NaCl (DS-HS) or low-salt diet containing 0.2% NaCl (DS-LS), and Dahl salt-resistant rats fed the same diets (DR-HS, DR-LS). 11betaHSD was investigated in colon, aorta, renal cortex, and renal medulla and was assessed as percentage conversion of [3H]corticosterone to [3H]11-dehydrocorticosterone in the presence of NAD or NADP. The results demonstrated that genotype exerts a significant effect on 11betaHSD. 11betaHSD activity was significantly increased in colon and renal medulla of SHR compared with WKY rats. No significant differences were observed in renal cortex and aorta. In Dahl rats kept on a low-salt diet, 11betaHSD activity was significantly higher in colon, renal medulla, and cortex of DS-LS than in DR-LS rats but no difference was observed in aorta. The differences disappeared in age-matched DS and DR rats fed the high-salt diet. Increased dietary sodium intake stimulated the activity of 11betaHSD in renal cortex and medulla of DR rats and decreased the activity in colon of DS rats. We conclude that the development of spontaneous and salt-induced hypertension is not associated with decreased activity of 11betaHSD. However, the results showed that salt intake is able to modulate the activity of 11betaHSD and that 11betaHSD in DS and DR rats responds to high dietary salt intake in a different manner.
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PMID:11Beta-hydroxysteroid dehydrogenase activity in spontaneously hypertensive and Dahl rats. 1095 Apr 2

Angiotensin II (ANG II) has multiple effects on cardiovascular and renal cells, including vasoconstriction, cell growth, induction of proinflammatory cytokines, and profibrogenic actions. Recent studies provide evidence that ANG II could stimulate intracellular formation of reactive oxygen species (ROS) such as the superoxide anion (O2-). This ANG II-mediated ROS formation exhibits different kinetic and lower absolute concentrations than those traditionally observed during the respiratory burst of phagocytic cells, but it likely involves similar membrane-bound NAD(P)H-oxidases. Current evidence suggests that ANG II, through AT1-receptor activation, upregulates several subunits of this multienzyme complex, resulting in an increase in intracellular O2- concentration. ROS are involved in several signal pathways, and redox-sensitive transcriptional factors (AP-1, NF-kappaB) have been characterized. ANG II-induced ROS play a pivotal role in several pathophysiologic situations of vascular and renal cells such as hypertension, endothelial dysfunction, nitrate tolerance, atherosclerosis, and cellular remodeling. Although these perceptions suggest that drugs interfering with ANG II effects (ACE inhibitors, AT1 -receptor antagonist) may serve as antioxidants, preventing vascular and renal changes, the clinical studies are not so straightforward. In fact, only specific risk groups, such as patients with diabetes mellitus or renal insufficiency, may benefit from ACE inhibitors, whereas hard endpoints showed no advantage for ACE inhibitors in patients with essential hypertension.
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PMID:Free radical production and angiotensin. 1098 Nov 45

Emerging evidence indicates that reactive oxygen species, especially superoxide and hydrogen peroxide, are important signaling molecules in cardiovascular cells. Their production is regulated by hormone-sensitive enzymes such as the vascular NAD(P)H oxidases, and their metabolism is coordinated by antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase. Both of these reactive oxygen species serve as second messengers to activate multiple intracellular proteins and enzymes, including the epidermal growth factor receptor, c-Src, p38 mitogen-activated protein kinase, Ras, and Akt/protein kinase B. Activation of these signaling cascades and redox-sensitive transcription factors leads to induction of many genes with important functional roles in the physiology and pathophysiology of vascular cells. Thus, reactive oxygen species participate in vascular smooth muscle cell growth and migration; modulation of endothelial function, including endothelium-dependent relaxation and expression of a proinflammatory phenotype; and modification of the extracellular matrix. All of these events play important roles in vascular diseases such as hypertension and atherosclerosis, suggesting that the sources of reactive oxygen species and the signaling pathways that they modify may represent important therapeutic targets.
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PMID:Modulation of protein kinase activity and gene expression by reactive oxygen species and their role in vascular physiology and pathophysiology. 1103 Dec 1


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