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)

A syndrome is described whose features, suggestive of primary mineralcorticoid excess, included hypertension, hypokalemia, low PRA, and responsiveness to spironolactone. Aldosterone levels were subnormal but as yet there has been no evidence of overproduction of other mineralocorticoids by chemical analysis or by bioassay of plasma and urinary extracts. The steroidal abnormalities that were observed involved peripheral matabolism rather than secretion. One patient exhibited a transient delay in reduction of the 3-keto group in the A ring, and both patients exhibited a decrease in the metabolism of cortisol to biologically inactive cortisone. This was shown by the marked decrease in the excretion of urinary metabolites bearing an 11-keto group and a decrease in the oxidation of 11 alpha-[3H]cortisol to tritiated water. The defect appeared not to be a deficiency of the 11 beta-oxidoreductase system itself, since the reverse reaction of conversion of cortisone to cortisol proceeded normally, but, rater, an alteration in the equilibrium position of 11 beta-oxidoreduction in favor of the reduced form. This was also expressed by a prolongation of the half-time of disappearance of cortisol. The decrease in the MCR permitted the maintenance of normal cortisol plasma levels and normal glucocorticoid function at a diminished rate of secretion. The decreased rate of conversion of cortisol to cortisone serves as a biochemical marker of this hypertensive syndrome.
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PMID:A syndrome of apparent mineralocorticoid excess associated with defects in the peripheral metabolism of cortisol. 22 61

Vascular smooth muscle (VSM) contains a bidirectional isoform of 11beta-hydroxysteroid dehydrogenase (11beta-HSD), the enzyme that can metabolize endogenous glucocorticoids to their respective 11-dehydro derivatives. 11BetaOH-progesterone (11betaOH-P), a compound that can be produced in vivo, is as potent or more potent than licorice derivatives in inhibiting renal and hepatic 11beta-HSD. When studied in homogenates prepared from primary cultures of rat VSM, 11betaOH-P and its derivative, 11-keto-progesterone (11-keto-P), proved to be potent, directionally specific inhibitors of vascular 11beta-HSD. 11BetaOH-P selectively inhibited the forward dehydrogenase reaction (corticosterone-->11-dehydrocorticosterone), whereas 11-keto-P selectively blocked the reverse oxidoreductase reaction. To test the physiological effects, vascular rings were prepared from rat aorta. Rings were incubated in culture media containing either a submaximal concentration of corticosterone (10 nmol/L), 11-dehydrocorticosterone (100 nmol/L), 11betaOH-P (1 micromol/L), 11-keto-P (1 micromol/L), or a combination of glucocorticoid and inhibitor for 24 hours. After the 24-hour incubation, rings were briefly stimulated sequentially with phenylephrine (10 nmol/L to 1 micromol/L) and angiotensin II (1 micromol/L). The immediate contractile response in rings incubated with both corticosterone and 11betaOH-P was greater than in rings previously incubated with either the corticosterone or 11betaOH-P alone (eg, response to 100 nmol/L phenylephrine in milligrams of force, mean+/-SE: corticosterone, 728+/-56, n=9; 11betaOH-P, 325+/-105, n=4; both, 1132+/-122, n=8; corticosterone versus both, P<.01). In contrast, the immediate contractile responses to phenylephrine and to angiotensin II were attenuated in rings exposed previously to both 11-dehydrocorticosterone and 11-keto-P. Thus, 11betaOH-P and 11-keto-P (and possibly structurally similar compounds) alter the vascular effects of glucocorticoids and may play a role in glucocorticoid-induced hypertension.
Hypertension 1997 Sep
PMID:11BetaOH-progesterone affects vascular glucocorticoid metabolism and contractile response. 931 31

Local tissue concentrations of glucocorticoids are modulated by the enzyme 11beta-hydroxysteroid dehydrogenase which interconverts cortisol and the inactive glucocorticoid cortisone in man, and corticosterone and 11-dehydrocorticosterone in rodents. The type I isoform (11beta-HSD1) is a bidirectional enzyme but acts predominantly as a oxidoreductase to form the active glucocorticoids cortisol or corticosterone, while the type II enzyme (11beta-HSD2) acts unidirectionally producing inactive 11-keto metabolites. There are no known clinical conditions associated with 11beta-HSD1 deficiency, but gene deletion experiments in the mouse indicate that this enzyme is important both for the maintenance of normal serum glucocorticoid levels, and in the activation of key hepatic gluconeogenic enzymes. Other important sites of action include omental fat, the ovary, brain and vasculature. Congenital defects in the 11beta-HSD2 enzyme have been shown to account for the syndrome of apparent mineralocorticoid excess (AME), a low renin severe form of hypertension resulting from the overstimulation of the non-selective mineralocorticoid receptor by cortisol in the distal tubule of the kidney. Inactivation of the 11beta-HSD2 gene in mice results in a phenotype with similar features to AME. In addition, these mice show high neonatal mortality associated with marked colonic distention, and remarkable hypertrophy and hyperplasia of the distal tubule epithelia. 11Beta-HSD2 also plays an important role in decreasing the exposure of the fetus to the high levels of maternal glucocorticoids. Recent work suggests a role for 11beta-HSD2 in non-mineralocorticoid target tissues where it would modulate glucocorticoid access to the glucocorticoid receptor, in invasive breast cancer and as a mechanism providing ligand for the putative 11-dehydrocorticosterone receptor. While previous homologies between members of the SCAD superfamily have been of the order of 20-30% phylogenetic analysis of a new branch of retinol dehydrogenases indicates identities of > 60% and overlapping substrate specificities. The availability of crystal structures of family members has allowed the mapping of conserved 11beta-HSD domains A-D to a cleft in the protein structure (cofactor binding domain), two parallel beta-sheets, and an alpha-helix (active site), respectively.
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PMID:The type I and type II 11beta-hydroxysteroid dehydrogenase enzymes. 1041 17

Paenibacillus A11-2 can efficiently cleave two carbon&bond;sulfur bonds in dibenzothiophene (DBT) and alkyl DBTs, which are refractory by conventional petroleum hydrodesulfurization, to remove sulfur atom at high temperatures. An 8.7-kb DNA fragment containing the genes for the DBT desulfurizing enzymes of A11-2 was cloned in Escherichia coli and characterized. Heterologous expression analysis of the deletion mutants identified three open reading frames that were required for the desulfurization of DBT to 2-hydroxybiphenyl (2-HBP). The three genes were designated tdsA, tdsB, and tdsC (for thermophilic desulfurization). Both the nucleotide sequences and the deduced amino acid sequences show significant homology to dszABC genes of Rhodococcus sp. IGTS8, but there are several local differences between them. Subclone analysis revealed that the product of tdsC oxidizes DBT to DBT-5,5'-dioxide via DBT-5-oxide, the product of tdsA converts DBT-5,5'-dioxide to 2-(2-hydroxyphenyl) benzene sulfinate, and the product of tdsB converts 2-(2-hydroxyphenyl)benzene sulfinate to 2-HBP. Cell-free extracts of a recombinant E. coli harboring all the three desulfurization genes converted DBT to 2-HBP at both 37 and 50 degrees C. In vivo and in vitro exhibition of desulfurization activity of the recombinant genes derived from a Paenibacillus indicates that an E. coli oxidoreductase can be functionally coupled with the monooxygenases of a gram-positive thermophile.
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PMID:Operon structure and functional analysis of the genes encoding thermophilic desulfurizing enzymes of Paenibacillus sp. A11-2. 1073 8

Hypertension, a disease with a high incidence in the population, affects all parts of the cardiovascular system. Studying the alteration of vasomotor responses of microvessels of hypertensive animals or responses of vessels following short-term increases in hemodynamic forces helps us to better understand the underlying cellular signaling events responsible for their functional adaptation. These adaptations are likely to precede the structural remodeling of arterioles, resulting in irreversible increases in peripheral vascular resistance in hypertension. Although malfunction of several mechanisms can lead to the development of hypertension, hemodynamic forces (such as pressure and shear stress) are increased in all forms of hypertension. Thus, local mechanisms that sense the level of these forces and transduce the signals into vasomotor responses must be affected in all forms of hypertension. The endothelium has a central role in the early functional adaptations. Pressure-induced myogenic constriction is enhanced due to the augmented release of endothelium-derived constrictor factors that modulate arteriolar smooth muscle sensitivity to Ca(2+). In contrast, flow/shear stress-induced dilation of arterioles is reduced in hypertension, due to the impaired mediation of the response by nitric oxide (NO). The magnitude of impairment is gender specific, primarily due to an estrogen-dependent enhancement of NO release in females. It is proposed that the elevated hemodynamic forces present in hypertension may themselves initiate these alterations, probably by enhancing the release of reactive oxygen species (ROS; produced by xanthine oxidase, NAD(P)H oxidoreductase, eNOS, etc.), which then interfere with the synthesis and/or action of endothelium-derived mediators. Interfering early on with these mechanisms may prevent the development of irreversible structural changes of the microcirculation observed in hypertension.
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PMID:Signaling pathways of mechanotransduction in arteriolar endothelium and smooth muscle cells in hypertension. 1215 4

The short-chain oxidoreductase (SCOR) family of enzymes includes over 2000 members identified in sequenced genomes. Of these enzymes, approximately 200 have been characterized functionally, and the three-dimensional crystal structures of approximately 40 have been reported. Since some SCOR enzymes are involved in hypertension, diabetes, breast cancer, and polycystic kidney disease, it is important to characterize the other members of the family for which the biological functions are currently unknown. Although the SCOR family appears to have only a single fully conserved residue, it was possible, using bioinformatics methods, to determine characteristic fingerprints composed of 30-40 residues that are conserved at the 70% or greater level in SCOR subgroups. These fingerprints permit reliable prediction of several important structure-function features including NAD/NADP cofactor preference. For example, the correlation of aspartate or arginine residues with NAD or NADP binding, respectively, predicts the cofactor preference of more than 70% of the SCOR proteins with unknown function. The analysis of conserved residues surrounding the cofactor has revealed the presence of previously undetected CH em leader O hydrogen bonds in the majority of the SCOR crystal structures, predicts the presence of similar hydrogen bonds in 90% of the SCOR proteins of unknown function, and suggests that these hydrogen bonds may play a critical role in the catalytic functions of these enzymes.
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PMID:Rational proteomics I. Fingerprint identification and cofactor specificity in the short-chain oxidoreductase (SCOR) enzyme family. 1463 34

Diminished activity of peroxisome proliferator-activated receptor-gamma (PPARgamma) may play a role in the pathogenesis of hypertension and vascular dysfunction. To better understand what genes are regulated by PPARgamma, an experimental data set was generated by microarray analysis, in duplicate, of pooled aortic mRNA isolated from mice treated for 21 days with a PPARgamma agonist (rosiglitazone) or vehicle. Of the 12,488 probe sets present on the array (Affymetrix MG-U74Av2), 181 were differentially expressed between groups according to a statistical metric generated using Affymetrix software. A significant correlation was observed between the microarray results and real-time RT-PCR analysis of 39 of these genes. Cluster analysis revealed 3 expression patterns, 29 transcripts of moderate abundance that were decreased (-93%) to very low levels, 106 transcripts that were downregulated (-42%), and 46 transcripts that were upregulated (+70%). Functional groups that were decreased included inflammatory response (-93%, n = 6), immune response (-86%, n = 7), and cytokines (-82%, n = 7). There was an overall upregulation in the oxidoreductase activity group (+47%, n = 9). Individually, six transcripts in this group were increased (+72%), and three were decreased (-34%). Fourteen of the genes map to regions in the rat genome that have been linked to increased blood pressure, and of 142 upstream regions analyzed, sequences resembling the DNA binding site for PPARgamma were identified in 101 of the differentially expressed genes.
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PMID:Gene expression profiling of potential PPARgamma target genes in mouse aorta. 1505 41

Androgens and estrogens are primarily made from dehydroepiandrosterone (DHEA), which is made from cholesterol via four steps. First, cholesterol enters the mitochondria with the assistance of the steroidogenic acute regulatory protein (StAR). Mutations in the StAR gene cause congenital lipoid adrenal hyperplasia (lipoid CAH), a potentially lethal disease in which virtually no steroids are made. Lipoid CAH is common among Palestinian Arabs and people from eastern Arabia, and among Korean and Japanese people. Second, within the mitochondria, cholesterol is converted to pregnenolone by the cholesterol side chain cleavage enzyme, P450scc; disorder of this enzyme is very rare, probably due to embryonic lethality. Third, pregnenolone undergoes 17alpha-hydroxylation by microsomal P450c17. 17alpha-Hydroxylase deficiency, manifesting as female sexual infantilism and hypertension, is rare except in Brazil. Finally, 17-OH pregnenolone is converted to DHEA by the 17,20 lyase activity of P450c17. The ratio of the 17,20 lyase to 17alpha-hydroxylase activity of P450c17 determines the ratio of C21 to C19 steroids produced. This ratio is regulated posttranslationally by at least three factors: the abundance of the electron-donating protein P450 oxidoreductase (POR), the presence of cytochrome b5 and the serine phosphorylation of P450c17. Mutations of POR are a new, recently described disorder manifesting as the Antley-Bixler skeletal dysplasia syndrome, and a form of polycystic ovary syndrome.
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PMID:Disorders of androgen synthesis--from cholesterol to dehydroepiandrosterone. 1610 14

The short-chain oxidoreductase (SCOR) family of enzymes includes over 6,000 members identified in sequenced genomes. Of these enzymes, approximately 300 have been characterized functionally, and the three-dimensional crystal structures of approximately 40 have been reported. Since some SCOR enzymes are steroid dehydrogenases involved in hypertension, diabetes, breast cancer, and polycystic kidney disease, it is important to characterize the other members of the family for which the biological functions are currently unknown and to determine their three-dimensional structure and mechanism of action. Although the SCOR family appears to have only a single fully conserved residue, it was possible, using bioinformatics methods, to determine characteristic fingerprints composed of 30-40 residues that are conserved at the 70% or greater level in SCOR subgroups. These fingerprints permit reliable prediction of several important structure-function features including cofactor preference, catalytic residues, and substrate specificity. Human type 1 3beta-hydroxysteroid dehydrogenase isomerase (3beta-HSDI) has 30% sequence identity with a human UDP galactose 4-epimerase (UDPGE), a SCOR family enzyme for which an X-ray structure has been reported. Both UDPGE and 3-HSDI appear to trace their origins back to bacterial 3alpha,20beta-HSD. Combining three-dimensional structural information and sequence data on the 3alpha,20beta-HSD, UDPGE, and 3beta-HSDI subfamilies with mutational analysis, we were able to identify the residues critical to the dehydrogenase function of 3-HSDI. We also identified the residues most probably responsible for the isomerase activity of 3beta-HSDI. We test our predictions by specific mutations based on sequence analysis and our structure-based model.
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PMID:Determining structure and function of steroid dehydrogenase enzymes by sequence analysis, homology modeling, and rational mutational analysis. 1646 63

Macrophage migration inhibitory factor acts via its intrinsic thiol-protein oxidoreductase activity to negatively regulate the neuronal chronotropic actions of angiotensin II in normotensive rat neurons. Because the chronotropic action of angiotensin II is potentiated in spontaneously hypertensive rat neurons, we investigated whether this negative regulatory mechanism is absent in these rats. Angiotensin II (100 nM) elicited an approximately 89% increase in neuronal firing in Wistar-Kyoto rat hypothalamus and brain stem cultured neurons and an increase in intracellular macrophage migration inhibitory factor levels in the same cells. The chronotropic action of angiotensin II was significantly greater (approximately 212% increase) in spontaneously hypertensive rat neurons, but angiotensin II failed to alter macrophage migration inhibitory factor expression in these cells. Intracellular application of recombinant macrophage migration inhibitory factor (0.8 nM) or its specific neuronal overexpression via Ad5-SYN-MIF (1x10(7) infectious units) significantly attenuated the chronotropic action of angiotensin II in spontaneously hypertensive rat neurons, similar to results from Wistar-Kyoto rat neurons. In contrast, C60S-macrophage migration inhibitory factor (0.8 nM), which lacks thiol-protein oxidoreductase activity, failed to alter the chronotropic action of angiotensin II in neurons from either rat strain. Thus, whereas macrophage migration inhibitory factor has the potential to depress the chronotropic action of angiotensin II in spontaneously hypertensive rat neurons, it is unlikely that this regulatory mechanism occurs, because angiotensin II does not increase the expression of this protein. The lack of this regulatory mechanism may contribute to the increased chronotropic action of angiotensin II in spontaneously hypertensive rat neurons.
Hypertension 2007 Mar
PMID:Lack of macrophage migration inhibitory factor regulation is linked to the increased chronotropic action of angiotensin II in SHR neurons. 1726 48


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