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ß2 -adrenergic receptor Thr164IIe polymorphism, blood pressure and ischaemic heart disease in 66?750 individuals.

https://arctichealth.org/en/permalink/ahliterature131722
Source
J Intern Med. 2012 Mar;271(3):305-14
Publication Type
Article
Date
Mar-2012
Author
M. Thomsen
M. Dahl
A. Tybjaerg-Hansen
B G Nordestgaard
Author Affiliation
Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
Source
J Intern Med. 2012 Mar;271(3):305-14
Date
Mar-2012
Language
English
Publication Type
Article
Keywords
Aged
Blood Pressure - genetics
Cross-Sectional Studies
Denmark
Female
Genetic Predisposition to Disease - genetics
Genotype
Humans
Hypertension - genetics
Male
Middle Aged
Muscle, Skeletal
Myocardial Ischemia - genetics
Myocytes, Smooth Muscle
Polymorphism, Single Nucleotide
Prospective Studies
Questionnaires
Receptors, Adrenergic, beta-2 - genetics
Sex Factors
Abstract
The ß(2) -adrenergic receptor (ADRB2) is located on smooth muscle cells and is an important regulator of smooth muscle tone. The Thr164Ile polymorphism (rs1800888) in the ADRB2 gene is rare but has profound functional consequences on receptor function and could cause lifelong elevated smooth muscle tone. We tested the hypothesis that Thr164Ile is associated with increased blood pressure, increased frequency of hypertension and increased risk of cardiovascular disease (CVD).
A total of 66 750 individuals from two large Danish general population studies were genotyped, and 1943 Thr164Ile heterozygotes and 16 homozygotes were identified.
Thr164Ile genotype was associated with increased systolic and diastolic blood pressure in women (trend: P = 0.04 and 0.02): systolic and diastolic blood pressure increased by 5% and 2%, respectively, in female homozygotes compared with female noncarriers. All female Thr164Ile homozygotes had hypertension compared with 58% of female heterozygotes and 54% of female noncarriers (chi-square: P = 0.001). Female Thr164Ile homozygotes and heterozygotes had odds ratios for ischaemic heart disease (IHD) of 2.93 (0.56-15.5) and 1.28 (1.03-1.61), respectively, compared with female noncarriers (trend: P = 0.007). These differences were not observed in men. Furthermore, Gly16Arg (rs1042713) and Gln27Glu (rs1042714) in the ADRB2 gene were not associated with blood pressure, hypertension or CVD either in the population overall or in women and men separately.
ADRB2 Thr164Ile is associated with increased blood pressure, increased frequency of hypertension and increased risk of IHD amongst women in the general population. These findings, particularly for homozygotes, are novel.
PubMed ID
21883537 View in PubMed
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Characterization of a common susceptibility locus for asthma-related traits.

https://arctichealth.org/en/permalink/ahliterature180651
Source
Science. 2004 Apr 9;304(5668):300-4
Publication Type
Article
Date
Apr-9-2004
Author
Tarja Laitinen
Anne Polvi
Pia Rydman
Johanna Vendelin
Ville Pulkkinen
Paula Salmikangas
Siru Mäkelä
Marko Rehn
Asta Pirskanen
Anna Rautanen
Marco Zucchelli
Harriet Gullstén
Marina Leino
Harri Alenius
Tuula Petäys
Tari Haahtela
Annika Laitinen
Catherine Laprise
Thomas J Hudson
Lauri A Laitinen
Juha Kere
Author Affiliation
GeneOS Limited, 00251 Helsinki, Finland.
Source
Science. 2004 Apr 9;304(5668):300-4
Date
Apr-9-2004
Language
English
Publication Type
Article
Keywords
Algorithms
Alternative Splicing
Animals
Asthma - genetics - metabolism
Bronchi - chemistry - cytology
Chromosomes, Human, Pair 7 - genetics
Epithelial Cells - chemistry
Female
Finland
Gene Expression
Genes
Genetic Linkage
Genetic Predisposition to Disease
Genetic Variation
Genotype
Haplotypes
Humans
Hypersensitivity - genetics - metabolism
Immunoglobulin E - blood
Inflammation - genetics
Lung - metabolism
Male
Mice
Myocytes, Smooth Muscle - chemistry
Polymorphism, Single Nucleotide
Quebec
Receptors, G-Protein-Coupled - analysis - genetics
Abstract
Susceptibility to asthma depends on variation at an unknown number of genetic loci. To identify susceptibility genes on chromosome 7p, we adopted a hierarchical genotyping design, leading to the identification of a 133-kilobase risk-conferring segment containing two genes. One of these coded for an orphan G protein-coupled receptor named GPRA (G protein-coupled receptor for asthma susceptibility), which showed distinct distribution of protein isoforms between bronchial biopsies from healthy and asthmatic individuals. In three cohorts from Finland and Canada, single nucleotide polymorphism-tagged haplotypes associated with high serum immunoglobulin E or asthma. The murine ortholog of GPRA was up-regulated in a mouse model of ovalbumin-induced inflammation. Together, these data implicate GPRA in the pathogenesis of atopy and asthma.
Notes
Comment In: Science. 2004 Apr 9;304(5668):185-715073340
PubMed ID
15073379 View in PubMed
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Cigarette smoke and lipopolysaccharide induce a proliferative airway smooth muscle phenotype.

https://arctichealth.org/en/permalink/ahliterature97163
Source
Respir Res. 2010;11:48
Publication Type
Article
Date
2010
Author
Tonio Pera
Reinoud Gosens
Andries H Lesterhuis
Riham Sami
Marco van der Toorn
Johan Zaagsma
Herman Meurs
Author Affiliation
Department of Molecular Pharmacology, University Centre for Pharmacy, University of Groningen, Groningen, The Netherlands. t.pera@rug.nl
Source
Respir Res. 2010;11:48
Date
2010
Language
English
Publication Type
Article
Keywords
Airway Remodeling - drug effects
Animals
Cattle
Cell Proliferation - drug effects
Cells, Cultured
Cyclin D1 - metabolism
DNA Replication - drug effects
Dose-Response Relationship, Drug
Flavonoids - pharmacology
Imidazoles - pharmacology
Isometric Contraction - drug effects
Lipopolysaccharides - pharmacology
Methacholine Chloride - pharmacology
Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors - metabolism
Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors - metabolism
Muscle, Smooth - drug effects - pathology
Myocytes, Smooth Muscle - drug effects - pathology
Phenotype
Phosphorylation
Potassium Chloride - pharmacology
Protein Kinase Inhibitors - pharmacology
Pulmonary Disease, Chronic Obstructive - pathology - physiopathology
Pyrimidines - pharmacology
Smoke - adverse effects
Smoking - adverse effects
Time Factors
Tissue Culture Techniques
Trachea - drug effects - pathology
p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors - metabolism
Abstract
BACKGROUND: A major feature of chronic obstructive pulmonary disease (COPD) is airway remodelling, which includes an increased airway smooth muscle (ASM) mass. The mechanisms underlying ASM remodelling in COPD are currently unknown. We hypothesized that cigarette smoke (CS) and/or lipopolysaccharide (LPS), a major constituent of CS, organic dust and gram-negative bacteria, that may be involved in recurrent airway infections and exacerbations in COPD patients, would induce phenotype changes of ASM. METHODS: To this aim, using cultured bovine tracheal smooth muscle (BTSM) cells and tissue, we investigated the direct effects of CS extract (CSE) and LPS on ASM proliferation and contractility. RESULTS: Both CSE and LPS induced a profound and concentration-dependent increase in DNA synthesis in BTSM cells. CSE and LPS also induced a significant increase in BTSM cell number, which was associated with increased cyclin D1 expression and dependent on activation of ERK 1/2 and p38 MAP kinase. Consistent with a shift to a more proliferative phenotype, prolonged treatment of BTSM strips with CSE or LPS significantly decreased maximal methacholine- and KCl-induced contraction. CONCLUSIONS: Direct exposure of ASM to CSE or LPS causes the induction of a proliferative, hypocontractile ASM phenotype, which may be involved in airway remodelling in COPD.
PubMed ID
20429916 View in PubMed
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Immunopathways in giant cell arteritis and polymyalgia rheumatica.

https://arctichealth.org/en/permalink/ahliterature181565
Source
Autoimmun Rev. 2004 Jan;3(1):46-53
Publication Type
Article
Date
Jan-2004
Author
Cornelia M Weyand
Wei Ma-Krupa
Jörg J Goronzy
Author Affiliation
Department of Immunology, Guggenheim 401, Mayo Clinic, Rochester, MN, USA. weyand.cornelia@may.edu
Source
Autoimmun Rev. 2004 Jan;3(1):46-53
Date
Jan-2004
Language
English
Publication Type
Article
Keywords
Apoptosis - physiology
Giant Cell Arteritis - immunology
Granuloma - immunology
Humans
Macrophages - metabolism
Myocytes, Smooth Muscle - metabolism
Oxidative Stress
Polymyalgia Rheumatica - immunology
T-Lymphocytes - metabolism
Vasculitis - immunology
Abstract
Giant cell arteritis (GCA), a vasculitis that targets medium- and large-size arteries, is ranked as a medical emergency because of its potential to cause blindness and stroke. The typical lesions, granulomas in the vessel wall, are formed by IFN-gamma-producing CD4+ T cells and macrophages. CD4+ T cells undergo in situ activation in the adventitia, where they interact with indigenous dendritic cells. Tissue injury is mediated by several distinct sets of macrophages that are committed to diverse effector functions. The dominant tissue injury in the media results from oxidative stress and leads to smooth muscle cell apoptosis and nitration of endothelial cells. Macrophage-derived growth factors are instrumental in driving the response-to-injury program of the artery that causes intimal hyperplasia and vessel occlusion. Clinical manifestations are those of tissue ischemia or a syndrome of exuberant systemic inflammation. The vascular and the systemic components of GCA contribute differentially to the disease, leading to distinct clinical phenotypes of this arteritis. Immunologically most interesting is polymyalgia rheumatica, in which the systemic component is combined with aborted vasculitis, suggesting a role for artery-specific tolerance mechanisms.
PubMed ID
14871649 View in PubMed
Less detail

Intracranial aneurysm risk locus 5q23.2 is associated with elevated systolic blood pressure.

https://arctichealth.org/en/permalink/ahliterature125936
Source
PLoS Genet. 2012;8(3):e1002563
Publication Type
Article
Date
2012
Author
Emília Ilona Gaál
Perttu Salo
Kati Kristiansson
Karola Rehnström
Johannes Kettunen
Antti-Pekka Sarin
Mika Niemelä
Antti Jula
Olli T Raitakari
Terho Lehtimäki
Johan G Eriksson
Elisabeth Widen
Murat Günel
Mitja Kurki
Mikael von und Zu Fraunberg
Juha E Jääskeläinen
Juha Hernesniemi
Marjo-Riitta Järvelin
Anneli Pouta
Christopher Newton-Cheh
Veikko Salomaa
Aarno Palotie
Markus Perola
Author Affiliation
Public Health Genomics Unit, Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland. emilia.gaal@helsinki.fi
Source
PLoS Genet. 2012;8(3):e1002563
Date
2012
Language
English
Publication Type
Article
Keywords
Adult
Blood Pressure - genetics
Chromosomes, Human, Pair 5 - genetics
Cohort Studies
Female
Finland
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Intracranial Aneurysm - genetics
Male
Middle Aged
Muscle Proteins - genetics
Myocytes, Smooth Muscle - metabolism
Polymorphism, Single Nucleotide
Risk factors
Transcription Factors - genetics
Zinc Fingers - genetics
Abstract
Although genome-wide association studies (GWAS) have identified hundreds of complex trait loci, the pathomechanisms of most remain elusive. Studying the genetics of risk factors predisposing to disease is an attractive approach to identify targets for functional studies. Intracranial aneurysms (IA) are rupture-prone pouches at cerebral artery branching sites. IA is a complex disease for which GWAS have identified five loci with strong association and a further 14 loci with suggestive association. To decipher potential underlying disease mechanisms, we tested whether there are IA loci that convey their effect through elevating blood pressure (BP), a strong risk factor of IA. We performed a meta-analysis of four population-based Finnish cohorts (n(FIN)? = ?11 266) not selected for IA, to assess the association of previously identified IA candidate loci (n ?=? 19) with BP. We defined systolic BP (SBP), diastolic BP, mean arterial pressure, and pulse pressure as quantitative outcome variables. The most significant result was further tested for association in the ICBP-GWAS cohort of 200 000 individuals. We found that the suggestive IA locus at 5q23.2 in PRDM6 was significantly associated with SBP in individuals of European descent (p(FIN) ?=? 3.01E-05, p(ICBP-GWAS) ?= ?0.0007, p(ALL)? = ?8.13E-07). The risk allele of IA was associated with higher SBP. PRDM6 encodes a protein predominantly expressed in vascular smooth muscle cells. Our study connects a complex disease (IA) locus with a common risk factor for the disease (SBP). We hypothesize that common variants in PRDM6 can contribute to altered vascular wall structure, hence increasing SBP and predisposing to IA. True positive associations often fail to reach genome-wide significance in GWAS. Our findings show that analysis of traditional risk factors as intermediate phenotypes is an effective tool for deciphering hidden heritability. Further, we demonstrate that common disease loci identified in a population isolate may bear wider significance.
Notes
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PubMed ID
22438818 View in PubMed
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Matrix metalloproteinase 2 activation of transforming growth factor-beta1 (TGF-beta1) and TGF-beta1-type II receptor signaling within the aged arterial wall.

https://arctichealth.org/en/permalink/ahliterature82233
Source
Arterioscler Thromb Vasc Biol. 2006 Jul;26(7):1503-9
Publication Type
Article
Date
Jul-2006
Author
Wang Mingyi
Zhao Di
Spinetti Gaia
Zhang Jing
Jiang Li-Qun
Pintus Gianfranco
Monticone Robert
Lakatta Edward G
Author Affiliation
Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging/NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224-6825, USA. mingyiw@grc.nia.nih.gov
Source
Arterioscler Thromb Vasc Biol. 2006 Jul;26(7):1503-9
Date
Jul-2006
Language
English
Publication Type
Article
Keywords
Aging - metabolism - physiology
Animals
Aorta - metabolism - physiology
Biological Markers - metabolism
Collagen - biosynthesis
Endothelium, Vascular - metabolism
Fibronectins - biosynthesis
Matrix Metalloproteinase 2 - physiology
Muscle, Smooth, Vascular - cytology - metabolism
Myocytes, Smooth Muscle - metabolism
RNA, Messenger - metabolism
Rats
Rats, Inbred F344
Receptors, Transforming Growth Factor beta - metabolism
Signal Transduction - physiology
Smad Proteins - metabolism
Tissue Distribution
Transforming Growth Factor beta - genetics - metabolism
Transforming Growth Factor beta1
Abstract
OBJECTIVE: To study matrix metalloproteinase 2 (MMP-2) effects on transforming growth factor-beta1 (TGF-beta1) activation status and downstream signaling during arterial aging. METHODS AND RESULTS: Western blotting and immunostaining showed that latent and activated TGF-beta1 are markedly increased within the aorta of aged Fisher 344 cross-bred Brown Norway (30 months of age) rats compared with adult (8 months of age) rats. Aortic TGF-beta1-type II receptor (TbetaRII), its downstream molecules p-similar to mad-mother against decapentaplegic (SMAD)2/3 and SMAD4, fibronectin, and collagen also increased with age. Moreover, TGF-beta1 staining is colocalized with that of activated MMP-2 within the aged arterial wall and vascular smooth muscle cell (VSMC) in vitro, and this physical association was confirmed by coimmunoprecipitation. Incubation of young aortic rings ex vivo or VSMCs in vitro with activated MMP-2 enhanced active TGF-beta1, collagen, and fibronectin expression to the level of untreated old counterparts, and this effect was abolished via inhibitors of MMP-2. Interestingly, in old untreated rings or VSMCs, the increased TGF-beta1, fibronectin, and collagen were also substantially reduced by inhibition of MMP-2. CONCLUSIONS: Active TGF-beta1, its receptor, and receptor-mediated signaling increase within the aortic wall with aging. TGF-beta1 activation is dependent, in part at least, by a concomitant age-associated increase in MMP-2 activity. Thus, MMP-2-activated TGF-beta1, and subsequently TbetaRII signaling, is a novel molecular mechanism for arterial aging.
PubMed ID
16690877 View in PubMed
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Persistent ductus arteriosus in the Brown-Norway inbred rat strain.

https://arctichealth.org/en/permalink/ahliterature80903
Source
Pediatr Res. 2006 Oct;60(4):407-12
Publication Type
Article
Date
Oct-2006
Author
Bökenkamp Regina
Gittenberger-De Groot Adriana C
Van Munsteren Conny J
Grauss Robert W
Ottenkamp Jaap
Deruiter Marco C
Author Affiliation
Departments of Pediatric Cardiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
Source
Pediatr Res. 2006 Oct;60(4):407-12
Date
Oct-2006
Language
English
Publication Type
Article
Keywords
Animals
Ductus Arteriosus - abnormalities - pathology
Ductus Arteriosus, Patent - genetics - pathology
Elastin - analysis
Female
Myocytes, Smooth Muscle - pathology
Rats
Rats, Inbred BN - abnormalities - genetics
Abstract
Persistent ductus arteriosus (PDA) is a common cardiovascular anomaly in children caused by the pathologic persistence of the left sixth pharyngeal arch artery. The inbred Brown-Norway (BN) rat presents with increased vascular fragility due to an aortic elastin deficit resulting from decreased elastin synthesis. The strikingly high prevalence of PDA in BN rats in a pilot study led us to investigate this vascular anomaly in 12 adolescent BN rats. In all BN rats, a PDA was observed macroscopically, whereas a ligamentum arteriosum was found in adult controls. The macroscopic appearance of the PDA was tubular (n = 2), stenotic (n = 8), or diverticular (n = 2). The PDA had the structure of a muscular artery with intimal thickening. In the normal closing ductus of the neonatal controls, the media consisted of layers of smooth muscle cells (SMCs) intermingled with layers of elastin. The intima was thin and poor in elastin. By contrast, the media of PDA in BN rats elastin lamellae were absent and the intima contained many elastic fibers. The abnormal distribution of elastin in the PDA of BN rats suggests that impaired elastin metabolism is related to the persistence of the ductus and implicates a genetically determined factor that may link the PDA with aortic fragility.
PubMed ID
16940252 View in PubMed
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Repeated allergen inhalation induces cytoskeletal remodeling in smooth muscle from rat bronchioles.

https://arctichealth.org/en/permalink/ahliterature78936
Source
Am J Respir Cell Mol Biol. 2007 Jun;36(6):721-7
Publication Type
Article
Date
Jun-2007
Author
McVicker Clare G
Leung Sum-Yee
Kanabar Varsha
Moir Lyn M
Mahn Katharina
Chung K Fan
Hirst Stuart J
Author Affiliation
King's College London School of Medicine, MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, Division of Asthma, Allergy and Lung Biology, London, United kingdom.
Source
Am J Respir Cell Mol Biol. 2007 Jun;36(6):721-7
Date
Jun-2007
Language
English
Publication Type
Article
Keywords
Actins - metabolism
Allergens - immunology
Animals
Antineoplastic Agents - pharmacology
Asthma - immunology
Bicyclo Compounds, Heterocyclic - pharmacology
Bronchi - cytology - drug effects - immunology
Carbachol - pharmacology
Cells, Cultured
Cytoskeleton - drug effects - metabolism
Depsipeptides - pharmacology
Inhalation Exposure
Male
Muscle Contraction - drug effects - physiology
Muscle, Smooth - cytology - drug effects - metabolism
Myocytes, Smooth Muscle - cytology - drug effects - metabolism
Ovalbumin - administration & dosage - immunology
Rats
Thiazolidines - pharmacology
Abstract
Airway hyperresponsiveness (AHR) is associated with airway wall structural remodeling and alterations in airway smooth muscle (ASM) function. Previously, in bronchioles from Brown Norway rats challenged by repeated ovalbumin (OVA) inhalation, we have reported increased force generation and depletion of smooth muscle contractile proteins. Here, we investigated if cytoskeletal changes in smooth muscle could account for this paradox. Sensitized rats (n = 5/group) were repeatedly challenged with OVA or saline, and the lungs were removed 24 h after the last challenge. Levels of globular (G) and filamentous (F) actin in bronchioles were determined by DNase I inhibition and contraction assessed in intact small bronchioles using a myograph. DNase I inhibition assays showed that G-actin monomers were more abundant ( approximately 1F:2G) in extracts from resting small bronchioles from OVA- or saline-challenged animals. However, while contractile protein levels in bronchioles were reduced by OVA (P
PubMed ID
17272821 View in PubMed
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Role of protein kinase C alpha and cyclin D1 in the proliferation of airway smooth muscle in asthmatic rats.

https://arctichealth.org/en/permalink/ahliterature90830
Source
Chin Med J (Engl). 2008 Oct 20;121(20):2070-6
Publication Type
Article
Date
Oct-20-2008
Author
Qiao Li-fen
Xu Yong-jian
Liu Xian-sheng
Xie Jun-gang
Wang Jin
Du Chun-ling
Zhang Jian
Ni Wang
Chen Shi-xin
Author Affiliation
Department of Respiratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
Source
Chin Med J (Engl). 2008 Oct 20;121(20):2070-6
Date
Oct-20-2008
Language
English
Publication Type
Article
Keywords
Animals
Asthma - pathology
Cell Proliferation
Cyclin D1 - genetics - physiology
Lung - pathology
Male
Myocytes, Smooth Muscle - pathology
Protein Kinase C-alpha - genetics - physiology
RNA, Messenger - analysis
Rats
Rats, Inbred BN
Abstract
BACKGROUND: Airway smooth muscle (ASM) is suspected to be a determining factor in the structural change of asthma. However, the role of protein kinase C alpha (PKCalpha) and cyclin D1 involved in the dysfunction of ASM leading to asthmatic symptoms is not clear. In this study, the central role of PKCalpha and cyclin D1 in ASM proliferation in asthmatic rats was explored. METHODS: Thirty-six pathogen-free male Brown Norway (BN) rats were randomly divided into 2 groups: control groups (group N1, N2 and N3) and asthmatic groups (group A1, A2, and A3). Groups A1, A2 and A3 were challenged with ovalbumin (OA) for 2 weeks, 4 weeks and 8 weeks respectively. Control animals were exposed to an aerosolized sterile phosphate buffered saline (PBS). The ASM mass and nucleus numbers were studied to estimate the degree of airway remodeling by the hematoxylin-eosin staining method. PKCalpha and cyclin D1 expression in the ASM cells was detected by reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. The relation between PKCalpha and cyclin D1 was assessed by linear regression analysis. PKC agonist phorbol 12-myristate 13-acetate (PMA), PKC inhibitor Ro31-8220 and an antisense oligonucleotide against cyclin D1 (ASOND) were used to treat ASM cells (ASMCs) obtained from the 2 weeks asthmatic rats. The cyclin D1 protein expression level was detected by Western blotting. RESULTS: Compared with the control group, the PKCalpha and cyclin D1 mRNA levels were increased in the asthmatic group. Similar to RT-PCR results, immunohistochemistry analysis for PKCalpha and cyclin D1 expression revealed an increased production in ASMCs after allergen treatment for 2, 4 and 8 weeks compared with the respective control groups. No difference in expression of PKCalpha and cyclin D1 in ASM were found in the 2, 4 or 8 weeks asthmatic rats. There were significant positive correlations between PKCalpha and cyclin D1 expression, both transcriptionally (r = 0.944, P
PubMed ID
19080278 View in PubMed
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Sprouty2 is involved in male sex organogenesis by controlling fibroblast growth factor 9-induced mesonephric cell migration to the developing testis.

https://arctichealth.org/en/permalink/ahliterature82291
Source
Endocrinology. 2006 Aug;147(8):3777-88
Publication Type
Article
Date
Aug-2006
Author
Chi Lijun
Itäranta Petri
Zhang Shaobing
Vainio Seppo
Author Affiliation
Department of Biochemistry, University of Oulu, Finland.
Source
Endocrinology. 2006 Aug;147(8):3777-88
Date
Aug-2006
Language
English
Publication Type
Article
Keywords
3-Hydroxysteroid Dehydrogenases - genetics
Animals
Cell Movement - physiology
Endothelial Cells - physiology
Extracellular Signal-Regulated MAP Kinases - metabolism
Female
Fibroblast Growth Factor 9 - genetics - metabolism
Gene Expression Regulation, Developmental
Homeodomain Proteins - genetics
Laminin - genetics
Leydig Cells - physiology
Male
Mesonephros - cytology - embryology - physiology
Mice
Mice, Inbred Strains
Mice, Transgenic
Myocytes, Smooth Muscle - physiology
Organ Culture Techniques
PAX2 Transcription Factor - genetics
Pregnancy
Promoter Regions (Genetics) - physiology
Proteins - genetics - metabolism
Proto-Oncogene Proteins - genetics
Sex Differentiation - physiology
Testis - cytology - embryology - physiology
Wnt Proteins - genetics
Wolffian Duct - cytology - embryology - physiology
Abstract
Fibroblast growth factor 9 (FGF9) signal has a role in organogenesis of the mammalian testis by controlling migration of mesonephric cells to the XY gonad, but neither it nor the FGF receptors is expressed sex-specifically. Of the Sprouty genes encoding antagonists of receptor tyrosine kinases including FGFr, mSprouty2 expression was confined to the developing testis and mesonephros. Gain of SPROUTY2 function in the male genital ridge and mesonephros malformed the vas deferens and epididymis, and diminished the number of seminiferous tubules and interstitium associating with reduced mesonephric cell migration and Fgf9 expression in embryonic testis, whereas exogenous FGF9 signaling recovered mesonephric cell migration inhibited by SPROUTY2. These phenotypes associated also with the decreased expression of Sox9, Desert hedgehog, Hsd3beta, Platelet/endothelial cell adhesion molecule, and alpha-smooth muscle actin, which are markers of the Sertoli, Leydig, endothelial, and peritubular myoid cells of the developing testis. Based on these data, we propose that the Sprouty proteins are involved normally in mediating the sexually dimorphic signaling of FGF9 and controlling cell migration from the mesonephros during testis development.
PubMed ID
16675530 View in PubMed
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