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Seiichi P T Matsuda - One of the best experts on this subject based on the ideXlab platform.
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Lanosterol biosynthesis in plants
Archives of Biochemistry and Biophysics, 2006Co-Authors: Mariya D Kolesnikova, Silvia Lodeiro, Quanbo Xiong, Seiichi P T MatsudaAbstract:Abstract Plants biosynthesize sterols from cycloartenol using a pathway distinct from the animal and fungal route through Lanosterol. Described herein are genome-mining experiments revealing that Arabidopsis encodes, in addition to cycloartenol Synthase, an accurate Lanosterol Synthase ( LSS )—the first example of Lanosterol Synthases cloned from a plant. The coexistence of cycloartenol Synthase and Lanosterol Synthase implies specific roles for both cyclopropyl and conventional sterols in plants. Phylogenetic reconstructions reveal that Lanosterol Synthases are broadly distributed in eudicots but evolved independently from those in animals and fungi. Novel catalytic motifs establish that plant Lanosterol Synthases comprise a third catalytically distinct class of Lanosterol Synthase.
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A putative precursor of isomalabaricane triterpenoids from Lanosterol Synthase mutants.
Organic Letters, 2006Co-Authors: Silvia Lodeiro, William K. Wilson, Hui Shan, Seiichi P T MatsudaAbstract:Known Lanosterol Synthase mutants produce monocyclic or tetracyclic byproducts from oxidosqualene. We describe Erg7 Tyr510 mutants that cause partial substrate misfolding and generate a tricyclic byproduct. This novel triterpene, (13αH)-isomalabarica-14(27),17E,21-trien-3β-ol, is the likely biosynthetic precursor of isomalabaricane triterpenoids in sponges. The results suggest the facile evolution of protective triterpenoids in sessile animals.
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enzyme redesign two mutations cooperate to convert cycloartenol Synthase into an accurate Lanosterol Synthase
Journal of the American Chemical Society, 2005Co-Authors: Silvia Lodeiro, Tanja Schulzgasch, Seiichi P T MatsudaAbstract:Efforts to modify the catalytic specificity of enzymes consistently show that it is easier to broaden the substrate or product specificity of an accurate enzyme than to restrict the selectivity of one that is promiscuous. Described herein are experiments in which cycloartenol Synthase was redesigned to become a highly accurate Lanosterol Synthase. Several single mutants have been described that modify the catalytic specificity of cycloartenol to form some Lanosterol. Modeling studies were undertaken to identify combinations of mutations that cooperate to decrease the formation of products other than Lanosterol. A double mutant was constructed and characterized and was shown to cyclize oxidosqualene accurately to Lanosterol (99%). This catalytic change entailed both relocating polarity with a His477Asn mutation and modifying steric constraints with an Ile481Val mutation.
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directed evolution experiments reveal mutations at cycloartenol Synthase residue his477 that dramatically alter catalysis
Organic Letters, 2002Co-Authors: Michael J R Segura, Silvia Lodeiro, And Akash J Patel, Michelle M Meyer, Seiichi P T MatsudaAbstract:Cycloartenol Synthase cyclizes and rearranges oxidosqualene to the protosteryl cation and then specifically deprotonates from C-19. To identify mutants that deprotonate differently, randomly generated mutant cycloartenol Synthases were selected in a yeast Lanosterol Synthase mutant. A novel His477Asn mutant was uncovered that produces 88% Lanosterol and 12% parkeol. The His477Gln mutant produces 73% parkeol, 22% Lanosterol, and 5% Δ7-Lanosterol. These are the most accurate Lanosterol Synthase and parkeol Synthase that have been generated by mutagenesis.
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directed evolution to generate cycloartenol Synthase mutants that produce Lanosterol
Organic Letters, 2002Co-Authors: Michelle M Meyer, And Ran Xu, Seiichi P T MatsudaAbstract:Cycloartenol Synthase converts oxidosqualene to cycloartenol, a pentacyclic isomer of the animal and fungal sterol precursor Lanosterol. We used directed evolution to find cycloartenol Synthase residues that affect cyclopropyl ring formation, selecting randomly generated cycloartenol Synthase mutants for their ability to genetically complement a yeast strain lacking Lanosterol Synthase. To increase the likelihood of finding novel mutations, the little-studied Dictyostelium discoideum cycloartenol Synthase was used for the mutagenesis. Several catalytically important residues were identified.
Yutaka Ebizuka - One of the best experts on this subject based on the ideXlab platform.
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protostadienol Synthase from aspergillus fumigatus functional conversion into Lanosterol Synthase
Biochemical and Biophysical Research Communications, 2010Co-Authors: Miki Kimura, Masaaki Shibuya, Tetsuo Kushiro, Yutaka EbizukaAbstract:abstract Oxidosqualene:protostadienol cyclase (OSPC) from the fungus Aspergillus fumigatus, catalyzes the cycliza-tion of (3S)-2,3-oxidosqualene into protosta-17(20)Z,24-dien-3b-ol which is theprecursor of the steroidalantibiotic helvolic acid. To shed light on the structure–function relationship between OSPC and oxido-squalene:Lanosterol cyclase (OSLC), we constructed an OSPC mutant in which the C-terminal residues 702 APPGGMR 708 were replaced with 702 NKSCAIS 708 , as in human OSLC. As a result, the mutant no longerproduced the protostadienol, but instead efficiently produced a 1:1 mixture of Lanosterol and parkeol.Thisis the first report of thefunctional conversion of OSPC into OSLC, which resulted ina 14-fold decreasein the V max /K M value, whereas the binding affinity for the substrate did not change significantly. Homol-ogy modeling suggested that stabilization of the C-20 protosteryl cation by the active-site Phe701through cation- p interactions is important for the product outcome between protostadienol andLanosterol. 2009 Elsevier Inc. All rights reserved.
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Protostadienol Synthase from Aspergillus fumigatus: functional conversion into Lanosterol Synthase.
Biochemical and Biophysical Research Communications, 2009Co-Authors: Miki Kimura, Masaaki Shibuya, Yutaka Ebizuka, Tetsuo Kushiro, Ikuro AbeAbstract:Oxidosqualene:protostadienol cyclase (OSPC) from the fungus Aspergillus fumigatus, catalyzes the cyclization of (3S)-2,3-oxidosqualene into protosta-17(20)Z,24-dien-3beta-ol which is the precursor of the steroidal antibiotic helvolic acid. To shed light on the structure-function relationship between OSPC and oxidosqualene:Lanosterol cyclase (OSLC), we constructed an OSPC mutant in which the C-terminal residues (702)APPGGMR(708) were replaced with (702)NKSCAIS(708), as in human OSLC. As a result, the mutant no longer produced the protostadienol, but instead efficiently produced a 1:1 mixture of Lanosterol and parkeol. This is the first report of the functional conversion of OSPC into OSLC, which resulted in a 14-fold decrease in the V(max)/K(M) value, whereas the binding affinity for the substrate did not change significantly. Homology modeling suggested that stabilization of the C-20 protosteryl cation by the active-site Phe701 through cation-pi interactions is important for the product outcome between protostadienol and Lanosterol.
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Identification of a product specific β-amyrin Synthase from Arabidopsis thaliana
Plant Physiology and Biochemistry, 2008Co-Authors: Masaaki Shibuya, Yuji Katsube, Ting Xiang, Miyuki Otsuka, Hong Zhang, Pimpimon Tansakul, Yutaka EbizukaAbstract:Triterpene skeletons are produced by oxidosqualene cyclases (OSCs). The genome sequencing of Arabidopsis thaliana revealed the presence of thirteen OSC homologous genes including At1g78950, which has been revised recently as two independent ORFs, namely At1g78950 and At1g78955. The cDNA corresponding to the revised At1g78950 was obtained by RT-PCR, ligated into Saccharomyces cerevisiae expression vector pYES2, and expressed in a Lanosterol Synthase deficient S. cerevisiae strain. LC-MS and NMR analyses of the accumulated product in the host cells showed that the product of At1g78950 is beta-amyrin, indicating that At1g78950 encodes a beta-amyrin Synthase (EC 5.4.99.-).
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Molecular cloning and functional expression of a multifunctional triterpene Synthase cDNA from a mangrove species Kandelia candel (L.) Druce
Phytochemistry, 2006Co-Authors: Mohammad Basyuni, Masaaki Shibuya, Shigeyuki Baba, Masashi Inafuku, Hirosuke Oku, Hironori Iwasaki, Keichiro Oshiro, Takafumi Okabe, Yutaka EbizukaAbstract:Abstract Homology based PCRs with degenerate primers designed from the conserved sequences among the known oxidosqualene cylases (OSCs) have resulted in cloning of a triterpene Synthase (KcMS) from the young roots of Kandelia candel (L.) Druce (Rhizophoraceae). KcMS consists of a 2286 bp open reading frame, which codes for 761 amino acids. The deduced amino acid sequence showed 79% homology to a lupeol Synthase from Ricinus communis suggesting it to be a lupeol Synthase of K. candel. KcMS was expressed in a Lanosterol Synthase deficient yeast with the expression vector pYES2 under the control of GAL1 promoter. GC–MS analysis showed that the transformant accumulated a mixture of lupeol, β-amyrin and α-amyrin in a 2:1:1 ratio, indicating that KcMS encodes a multifunctional triterpene Synthase, although it showed high sequence homology to a R. communis lupeol Synthase. This is the first OSC cloning from mangrove tree species.
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Constituents of Laurus nobilis L. inhibit recombinant human Lanosterol Synthase
Journal of Natural Medicines, 2005Co-Authors: Rie Tanaka, Masaaki Shibuya, Yuichi Sakano, Yutaka Ebizuka, Ken Shimizu, Yukihiro GodaAbstract:Extracts from 37 kinds of foods and foodstuffs were tested for inhibitory activity against recombinant human Lanosterol Synthase. Among them, extracts from five samples showed significant inhibition. Potent activity (55%) was found in 95% ethanol extract of Laurus nobilis L. Therefore, large-scale methanol extraction of the plant was carried out, and the constituents were separated by partition and fractionation by silica gel chromatography and HPLC. Four flavonoids, kaemperol 3-O-[2″,4″-O-di-E-p-coumaroyl-α-l-pyranorhamnoside] (1); 3,3′,4′,5,6,7,8-heptamethoxyflavone (2); 3′,4′,5,6,7,8-hexamethoxyflavone (nobiletin) (3); and 4′,5,6,7,8-pentamethoxyflavone (tangeretin) (4); and six sesquiterpens, eremanthine (5), dehydrocostus lactone (6), costunolide (7), zaluzanin C (8), zaluzanin D (9) and reynosin (10) were isolated. Eremanthine (5) showed the most potent activity, 70% inhibition, at the concentration of 500 μM.
Masaaki Shibuya - One of the best experts on this subject based on the ideXlab platform.
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protostadienol Synthase from aspergillus fumigatus functional conversion into Lanosterol Synthase
Biochemical and Biophysical Research Communications, 2010Co-Authors: Miki Kimura, Masaaki Shibuya, Tetsuo Kushiro, Yutaka EbizukaAbstract:abstract Oxidosqualene:protostadienol cyclase (OSPC) from the fungus Aspergillus fumigatus, catalyzes the cycliza-tion of (3S)-2,3-oxidosqualene into protosta-17(20)Z,24-dien-3b-ol which is theprecursor of the steroidalantibiotic helvolic acid. To shed light on the structure–function relationship between OSPC and oxido-squalene:Lanosterol cyclase (OSLC), we constructed an OSPC mutant in which the C-terminal residues 702 APPGGMR 708 were replaced with 702 NKSCAIS 708 , as in human OSLC. As a result, the mutant no longerproduced the protostadienol, but instead efficiently produced a 1:1 mixture of Lanosterol and parkeol.Thisis the first report of thefunctional conversion of OSPC into OSLC, which resulted ina 14-fold decreasein the V max /K M value, whereas the binding affinity for the substrate did not change significantly. Homol-ogy modeling suggested that stabilization of the C-20 protosteryl cation by the active-site Phe701through cation- p interactions is important for the product outcome between protostadienol andLanosterol. 2009 Elsevier Inc. All rights reserved.
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Protostadienol Synthase from Aspergillus fumigatus: functional conversion into Lanosterol Synthase.
Biochemical and Biophysical Research Communications, 2009Co-Authors: Miki Kimura, Masaaki Shibuya, Yutaka Ebizuka, Tetsuo Kushiro, Ikuro AbeAbstract:Oxidosqualene:protostadienol cyclase (OSPC) from the fungus Aspergillus fumigatus, catalyzes the cyclization of (3S)-2,3-oxidosqualene into protosta-17(20)Z,24-dien-3beta-ol which is the precursor of the steroidal antibiotic helvolic acid. To shed light on the structure-function relationship between OSPC and oxidosqualene:Lanosterol cyclase (OSLC), we constructed an OSPC mutant in which the C-terminal residues (702)APPGGMR(708) were replaced with (702)NKSCAIS(708), as in human OSLC. As a result, the mutant no longer produced the protostadienol, but instead efficiently produced a 1:1 mixture of Lanosterol and parkeol. This is the first report of the functional conversion of OSPC into OSLC, which resulted in a 14-fold decrease in the V(max)/K(M) value, whereas the binding affinity for the substrate did not change significantly. Homology modeling suggested that stabilization of the C-20 protosteryl cation by the active-site Phe701 through cation-pi interactions is important for the product outcome between protostadienol and Lanosterol.
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Identification of a product specific β-amyrin Synthase from Arabidopsis thaliana
Plant Physiology and Biochemistry, 2008Co-Authors: Masaaki Shibuya, Yuji Katsube, Ting Xiang, Miyuki Otsuka, Hong Zhang, Pimpimon Tansakul, Yutaka EbizukaAbstract:Triterpene skeletons are produced by oxidosqualene cyclases (OSCs). The genome sequencing of Arabidopsis thaliana revealed the presence of thirteen OSC homologous genes including At1g78950, which has been revised recently as two independent ORFs, namely At1g78950 and At1g78955. The cDNA corresponding to the revised At1g78950 was obtained by RT-PCR, ligated into Saccharomyces cerevisiae expression vector pYES2, and expressed in a Lanosterol Synthase deficient S. cerevisiae strain. LC-MS and NMR analyses of the accumulated product in the host cells showed that the product of At1g78950 is beta-amyrin, indicating that At1g78950 encodes a beta-amyrin Synthase (EC 5.4.99.-).
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Molecular cloning and functional expression of a multifunctional triterpene Synthase cDNA from a mangrove species Kandelia candel (L.) Druce
Phytochemistry, 2006Co-Authors: Mohammad Basyuni, Masaaki Shibuya, Shigeyuki Baba, Masashi Inafuku, Hirosuke Oku, Hironori Iwasaki, Keichiro Oshiro, Takafumi Okabe, Yutaka EbizukaAbstract:Abstract Homology based PCRs with degenerate primers designed from the conserved sequences among the known oxidosqualene cylases (OSCs) have resulted in cloning of a triterpene Synthase (KcMS) from the young roots of Kandelia candel (L.) Druce (Rhizophoraceae). KcMS consists of a 2286 bp open reading frame, which codes for 761 amino acids. The deduced amino acid sequence showed 79% homology to a lupeol Synthase from Ricinus communis suggesting it to be a lupeol Synthase of K. candel. KcMS was expressed in a Lanosterol Synthase deficient yeast with the expression vector pYES2 under the control of GAL1 promoter. GC–MS analysis showed that the transformant accumulated a mixture of lupeol, β-amyrin and α-amyrin in a 2:1:1 ratio, indicating that KcMS encodes a multifunctional triterpene Synthase, although it showed high sequence homology to a R. communis lupeol Synthase. This is the first OSC cloning from mangrove tree species.
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Lanosterol Synthase in dicotyledonous plants
Plant and Cell Physiology, 2006Co-Authors: Masashi Suzuki, Hikaru Seki, Yuji Katsube, Toshiya Muranaka, Kiyoshi Ohyama, Tetsuo Kushiro, Hiroaki Hayashi, Ting Xiang, Kazuki Saito, Masaaki ShibuyaAbstract:: Sterols are important as structural components of plasma membranes and precursors of steroidal hormones in both animals and plants. Plant sterols show a wide structural variety and significant structural differences from those of animals. To elucidate the origin of structural diversity in plant sterols, their biosynthesis has been extensively studied [Benveniste (2004) Annu. Rev. Plant. Biol. 55: 429, Schaller (2004) Plant Physiol. Biochem. 42: 465]. The differences in the biosynthesis of sterols between plants and animals begin at the step of cyclization of 2,3-oxidosqualene, which is cyclized to Lanosterol in animals and to cycloartenol in plants. However, here we show that plants also have the ability to synthesize Lanosterol directly from 2,3-oxidosqualene, which may lead to a new pathway to plant sterols. The Arabidopsis gene At3g45130, designated LAS1, encodes a functional Lanosterol Synthase in plants. A phylogenetic tree showed that LAS1 belongs to the previously uncharacterized branch of oxidosqualene cyclases, which differs from the cycloartenol Synthase branch. Panax PNZ on the same branch was also shown to be a Lanosterol Synthase in a yeast heterologous expression system. The higher diversity of plant sterols may require two biosynthetic routes in steroidal backbone formation.
John M Hamlyn - One of the best experts on this subject based on the ideXlab platform.
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Lanosterol Synthase gene polymorphisms and changes in endogenous ouabain in the response to low sodium intake
Hypertension, 2016Co-Authors: Chiara Lanzani, Lorena Citterio, Elisabetta Messaggio, Simona Delli Carpini, Marco Simonini, Nunzia Casamassima, Elena Brioni, Laura Zagato, G Gatti, John M HamlynAbstract:Circulating levels of endogenous ouabain (EO), a vasopressor hormone of adrenocortical origin, are increased by sodium depletion. Furthermore, Lanosterol Synthase, an enzyme involved in cholesterol biosynthesis, has a missense polymorphism (rs2254524 V642L) that affects EO biosynthesis in adrenocortical cells. Here, we investigated the hypothesis that Lanosterol Synthase rs2254524 alleles in vivo impact the blood pressure (BP) and EO responses evoked by a low dietary Na intake ( P =0.013) and diastolic BP (DBP: −5.1±0.98 versus −1.4±0.94 mm Hg; P P =0.028). In addition, BP rose in ≈25% of the patients in response to the low salt diet and this was associated with increased circulating EO. Lanosterol Synthase gene polymorphisms influence both the salt sensitivity of BP and changes in circulating EO in response to a low salt diet. The response of BP and EO to the low salt diet is markedly heterogeneous. Approximately 25% of patients experienced adverse effects, that is, increased BP and EO when salt intake was reduced and may be at increased long-term risk. The augmented response of EO to the low salt diet further supports the view that adrenocortical function is abnormal in some essential hypertensives.
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Lanosterol Synthase gene polymorphisms and changes in endogenous ouabain in the response to low sodium intake
Hypertension, 2016Co-Authors: Chiara Lanzani, Lorena Citterio, Elisabetta Messaggio, Simona Delli Carpini, Marco Simonini, Nunzia Casamassima, Elena Brioni, Laura Zagato, G Gatti, John M HamlynAbstract:Circulating levels of endogenous ouabain (EO), a vasopressor hormone of adrenocortical origin, are increased by sodium depletion. Furthermore, Lanosterol Synthase, an enzyme involved in cholesterol biosynthesis, has a missense polymorphism (rs2254524 V642L) that affects EO biosynthesis in adrenocortical cells. Here, we investigated the hypothesis that Lanosterol Synthase rs2254524 alleles in vivo impact the blood pressure (BP) and EO responses evoked by a low dietary Na intake (<100 mEq/d, 2 weeks) among patients with mild essential hypertension. During the low salt diet, the declines in both systolic BP (SBP: -8.7±1.7 versus -3.0±1.5; P=0.013) and diastolic BP (DBP: -5.1±0.98 versus -1.4±0.94 mm Hg; P<0.05), and the slope of the long-term pressure-natriuresis relationship affected significantly the presence of the Lanosterol Synthase rs2254524 A variant (AA: 0.71±0.22, AC 0.09±0.13, and CC 0.04±0.11 mEq/mm Hg/24 h; P=0.028). In addition, BP rose in ≈25% of the patients in response to the low salt diet and this was associated with increased circulating EO. Lanosterol Synthase gene polymorphisms influence both the salt sensitivity of BP and changes in circulating EO in response to a low salt diet. The response of BP and EO to the low salt diet is markedly heterogeneous. Approximately 25% of patients experienced adverse effects, that is, increased BP and EO when salt intake was reduced and may be at increased long-term risk. The augmented response of EO to the low salt diet further supports the view that adrenocortical function is abnormal in some essential hypertensives.
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Lanosterol Synthase Gene Polymorphisms and Changes in Endogenous Ouabain in the Response to Low Sodium Intake
Hypertension, 2015Co-Authors: Chiara Lanzani, Lorena Citterio, Elisabetta Messaggio, Marco Simonini, Nunzia Casamassima, Elena Brioni, Laura Zagato, G Gatti, Simona Delli Carpini, John M HamlynAbstract:Circulating levels of endogenous ouabain (EO), a vasopressor hormone of adrenocortical origin, are increased by sodium depletion. Furthermore, Lanosterol Synthase, an enzyme involved in cholesterol biosynthesis, has a missense polymorphism (rs2254524 V642L) that affects EO biosynthesis in adrenocortical cells. Here, we investigated the hypothesis that Lanosterol Synthase rs2254524 alleles in vivo impact the blood pressure (BP) and EO responses evoked by a low dietary Na intake (
Chiara Lanzani - One of the best experts on this subject based on the ideXlab platform.
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Abstract P122: Lanosterol Synthase (LSS) Gene As Predictor Of Kidney Dysfunction In Hypertensive Patients
Hypertension, 2020Co-Authors: Marco Simonini, Lorena Citterio, Elisabetta Messaggio, Chiara Lanzani, Simone Fontana, Sipontina Faienza, Chiara Maria Maggioni, Erika Salvi, Daniele Cusi, Paolo ManuntaAbstract:Recently we have proposed LSS as genotype-based risk stratification to predict accelerated eGFR decay in a prospective cohort study of essential HYP patients. We extract clinical data of a general population from HYPERGENES consortium. We also collect genetic data for LSS polymorphism that was already demonstrated as involved in kidney damage. A cohort of 3137 patients were selected. At different age, as expected, HYP status have a deep impact on eGFR. Indeed in young (age < 50ys) eGFR is higher in HYP vs control (86.2 ± 19.3 vs 82.7 ± 16.3 ml/min; p=0.04); vice-versa in elder (age > 65ys) HYP have a reduction in eGFR (55.7 ± 12.9 vs 71.0 ± 12.9 ml/min; p<0.001) and higher incidence of severe CKD (2.7% vs 0.1%; p=0.001). We do not observe a direct influence of LSS polymorphism of eGFR. When LSS is considered according to HYP status and age class it is possible to observe a preservation of age-associated eGFR reduction in normotensive patients (eGFR 91.4 vs 90.1 vs 81.8 at age classes for LSS risk allele); on the other side, LSS seems to enhance eGFR reduction associate to HYP status (eGFR 84.6 vs 75.6 vs 48.0 for LSS risk allele; p=0.032 after correction for covariates; see table for details and figure 1). Furthermore, our genomics lab just developed a LSS V642L Knock-in mouse model by CRISPR-Cas9 technique. The sequencing analysis confirmed the correct insertion of 643L mutation for both alleles in mice gene. The 642L LSS Knock-in mice at 1 month of age were viable, healthy and indistinguishable from the WT counterpart Conclusion: Patients caring the risk allele of this specific LSS polymorphism seems to express hyper-filtration if compared to their counterparts.
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Lanosterol Synthase genetic variants endogenous ouabain and both acute and chronic kidney injury
American Journal of Kidney Diseases, 2019Co-Authors: Rossella Iatrino, Lorena Citterio, Nunzia Casamassima, Chiara Lanzani, Laura Zagato, Elena Bignami, Roberta Meroni, Alberto Zangrillo, Ottavio Alfieri, Simone FontanaAbstract:Rationale & Objective Studies of humans and animals have suggested that endogenous ouabain (EO) and related genes are mediators of acute (AKI) and chronic kidney injury. We sought to examine the relationship among EO levels, genetic variants in Lanosterol Synthase (LSS; an enzyme that catalyzes synthesis of cholesterol, a precursor of EO), and both AKI and chronic kidney injury. Study Design 2 prospective observational cohort studies and a cross-sectional study of kidney tissue. Setting & Participants (1) A prospective cohort study of patients undergoing cardiovascular surgery, (2) measurement of EO concentration in kidney tissue removed because of an adjacent tumor, and (3) a prospective cohort study of patients with newly diagnosed essential hypertension. Exposure Missense variant in LSS (A instead of C allele at rs2254524), which leads to a valine to leucine substitution at amino acid 642. Outcomes Development of postoperative AKI in the cardiovascular surgery cohort, EO concentration in kidney tissue, and estimated glomerular filtration rate (eGFR) reductions in the essential hypertension cohort. Analytical Approach Logistic regression for analysis of postoperative AKI, analysis of variance for EO concentration in kidney tissue, and generalized linear models for changes in eGFR over time. Results AKI incidence following cardiovascular surgery was greater among those with the LSS rs2254524 AA genotype (30.7%) than in those with the CC genotype (17.4%; P=0.001). LSS rs2254524 AA kidneys had higher EO concentrations than CC kidneys (2.14±0.29 vs 1.25±0.08ng/g; P Limitations These associations do not necessarily represent causal relationships; LSS rs2254524 variants may have effects on other steroid hormones. Conclusions These findings support the potential value of LSS rs2254524 genotype–based risk stratification to identify patients at high risk for AKI before cardiovascular surgery, as well as predict accelerated eGFR in the setting of hypertension. These findings also suggest that LSS may in part drive EO-mediated kidney damage. EO may represent a new potential therapeutic target for the prevention of AKI and slowing of kidney damage in the setting of hypertension.
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Lanosterol Synthase gene polymorphisms and changes in endogenous ouabain in the response to low sodium intake
Hypertension, 2016Co-Authors: Chiara Lanzani, Lorena Citterio, Elisabetta Messaggio, Simona Delli Carpini, Marco Simonini, Nunzia Casamassima, Elena Brioni, Laura Zagato, G Gatti, John M HamlynAbstract:Circulating levels of endogenous ouabain (EO), a vasopressor hormone of adrenocortical origin, are increased by sodium depletion. Furthermore, Lanosterol Synthase, an enzyme involved in cholesterol biosynthesis, has a missense polymorphism (rs2254524 V642L) that affects EO biosynthesis in adrenocortical cells. Here, we investigated the hypothesis that Lanosterol Synthase rs2254524 alleles in vivo impact the blood pressure (BP) and EO responses evoked by a low dietary Na intake ( P =0.013) and diastolic BP (DBP: −5.1±0.98 versus −1.4±0.94 mm Hg; P P =0.028). In addition, BP rose in ≈25% of the patients in response to the low salt diet and this was associated with increased circulating EO. Lanosterol Synthase gene polymorphisms influence both the salt sensitivity of BP and changes in circulating EO in response to a low salt diet. The response of BP and EO to the low salt diet is markedly heterogeneous. Approximately 25% of patients experienced adverse effects, that is, increased BP and EO when salt intake was reduced and may be at increased long-term risk. The augmented response of EO to the low salt diet further supports the view that adrenocortical function is abnormal in some essential hypertensives.
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Lanosterol Synthase gene polymorphisms and changes in endogenous ouabain in the response to low sodium intake
Hypertension, 2016Co-Authors: Chiara Lanzani, Lorena Citterio, Elisabetta Messaggio, Simona Delli Carpini, Marco Simonini, Nunzia Casamassima, Elena Brioni, Laura Zagato, G Gatti, John M HamlynAbstract:Circulating levels of endogenous ouabain (EO), a vasopressor hormone of adrenocortical origin, are increased by sodium depletion. Furthermore, Lanosterol Synthase, an enzyme involved in cholesterol biosynthesis, has a missense polymorphism (rs2254524 V642L) that affects EO biosynthesis in adrenocortical cells. Here, we investigated the hypothesis that Lanosterol Synthase rs2254524 alleles in vivo impact the blood pressure (BP) and EO responses evoked by a low dietary Na intake (<100 mEq/d, 2 weeks) among patients with mild essential hypertension. During the low salt diet, the declines in both systolic BP (SBP: -8.7±1.7 versus -3.0±1.5; P=0.013) and diastolic BP (DBP: -5.1±0.98 versus -1.4±0.94 mm Hg; P<0.05), and the slope of the long-term pressure-natriuresis relationship affected significantly the presence of the Lanosterol Synthase rs2254524 A variant (AA: 0.71±0.22, AC 0.09±0.13, and CC 0.04±0.11 mEq/mm Hg/24 h; P=0.028). In addition, BP rose in ≈25% of the patients in response to the low salt diet and this was associated with increased circulating EO. Lanosterol Synthase gene polymorphisms influence both the salt sensitivity of BP and changes in circulating EO in response to a low salt diet. The response of BP and EO to the low salt diet is markedly heterogeneous. Approximately 25% of patients experienced adverse effects, that is, increased BP and EO when salt intake was reduced and may be at increased long-term risk. The augmented response of EO to the low salt diet further supports the view that adrenocortical function is abnormal in some essential hypertensives.
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Lanosterol Synthase Gene Polymorphisms and Changes in Endogenous Ouabain in the Response to Low Sodium Intake
Hypertension, 2015Co-Authors: Chiara Lanzani, Lorena Citterio, Elisabetta Messaggio, Marco Simonini, Nunzia Casamassima, Elena Brioni, Laura Zagato, G Gatti, Simona Delli Carpini, John M HamlynAbstract:Circulating levels of endogenous ouabain (EO), a vasopressor hormone of adrenocortical origin, are increased by sodium depletion. Furthermore, Lanosterol Synthase, an enzyme involved in cholesterol biosynthesis, has a missense polymorphism (rs2254524 V642L) that affects EO biosynthesis in adrenocortical cells. Here, we investigated the hypothesis that Lanosterol Synthase rs2254524 alleles in vivo impact the blood pressure (BP) and EO responses evoked by a low dietary Na intake (
