In order to find new informative predictors of myocardial infarction, we performed an analysis of genotype frequencies of polymorphic markers of SELE (rs2076059, 3832T > C), SELP (rs6131, S290 N), SELL (rs1131498, F206L), ICAM1 (rs5498, K469E), VCAM1 (rs3917010, c.928 + 420A > C), PECAM1 (rs668, V125L), VEGFA (rs35569394, -2549(18)I/D), CCL2 (rs1024611, -2518A > G), NOS3 (rs1799983, E298D), and DDAH1 (rs669173, c.303 + 30998A > G) genes in the group of Russian men with myocardial infarction (N = 315) and the control group of corresponding ethnicity, gender, and age (N = 286). Using Markov chain Monte-Carlo method (APSampler), we found genotype combinations associated with increased and decreased risk of myocardial infarction. The most significant associations were detected for PECAM1*V/V + DDAH1*C (OR = 4.17 CI 1.56-11.15 Pperm = 0.005) SELE*C + VEGFA*I + CCL2*G + VCAM1*A + NOS3*D (OR = 2.74 CI 1.66-4.52 Pperm = 2.09 × 10(-5)), and VEGFA*D/D + CCL2*A + DDAH1*C (OR = 0.44 CI 0.28-0.7 Pperm = 7.89 × 10(-5)) genotype combinations.

• Klíčová slova
• Genetic testing, Myocardial infarction, Risk prediction,
• MeSH
• amidohydrolasy genetika   MeSH
• antigeny CD31 genetika   MeSH
• dospělí MeSH
• frekvence genu MeSH
• genetická predispozice k nemoci MeSH
• genetické asociační studie MeSH
• genetické testování MeSH
• infarkt myokardu etnologie   genetika   MeSH
• jednonukleotidový polymorfismus MeSH
• lidé středního věku MeSH
• lidé MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Rusko MeSH
• Názvy látek
• amidohydrolasy MeSH
• antigeny CD31 MeSH
• dimethylargininase MeSH Prohlížeč

BACKGROUND: Cardiotrophin-1 (CT-1), a member of the IL-6 superfamily, is elevated in the serum of patients with ischemic and valvular heart disease. In this study, we hypothesized that CT-1 induces endothelial cell angiogenesis and that the ADMA/DDAH pathway plays an important role in the process. METHODS: pEGFP-N1-CTF1-GFP and pEGFP-N1 were constructed and used to transiently transfect to HUVECs, mediated by LipofectamineTM 2000. After transfection, the expression of CT-1 was examined by qRT-PCR and western blotting. Endothelial cell proliferation assay was evaluated using the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide (MTT) method. Migration assay was performed using transwell, tube formation test was examined on Matrigel, eNOSmRNA expression was assayed by qRT-PCR, DDAH I, DDAHII and VEGF expression were detected by western blotting, the level of ADMA and the activity of DDAH were measured by High Performance Liquid Chromatography, NOS activity and the concentration of NO were assayed by L-[3H] citrulline production from L-[3H]arginine. RESULTS: Overexpression of CT-1, increased endothelial cell proliferation, migration and formation of blood vessels, upregulated the expression of eNOSmRNA, DDAHI, DDAHII and VEGF, elevated the activity of DDAH and NOS, decreased the level of ADMA and promoted NO synthesis. In contrast, ADMA partially inhibited the effects of CT-1 induction. CONCLUSIONS: Overexpression of CT-1 increases cell proliferation, migration and formation of blood vessels. This result also suggests that CT-1 may regulate angiogenesis through the ADMA/DDAH pathway.

• Klíčová slova
• ADMA, DDAH, angiogenesis, cardiotrophin-1 (CT-1), eNOS,
• MeSH
• amidohydrolasy metabolismus   MeSH
• analýza buněčné migrace MeSH
• antigeny CD151 metabolismus   MeSH
• arginin analogy a deriváty   metabolismus   MeSH
• cévní endotel cytologie   MeSH
• cytokiny metabolismus   fyziologie   MeSH
• endoteliální buňky pupečníkové žíly (lidské) cytologie   MeSH
• fyziologická neovaskularizace fyziologie   MeSH
• kultivované buňky MeSH
• lidé MeSH
• messenger RNA metabolismus   MeSH
• oxid dusnatý metabolismus   MeSH
• pohyb buněk fyziologie   MeSH
• proliferace buněk MeSH
• signální transdukce fyziologie   MeSH
• synthasa oxidu dusnatého, typ III metabolismus   MeSH
• transfekce MeSH
• vaskulární endoteliální růstový faktor A metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• amidohydrolasy MeSH
• antigeny CD151 MeSH
• arginin MeSH
• cardiotrophin 1 MeSH Prohlížeč
• cytokiny MeSH
• dimethylargininase MeSH Prohlížeč
• messenger RNA MeSH
• N,N-dimethylarginine MeSH Prohlížeč
• oxid dusnatý MeSH
• synthasa oxidu dusnatého, typ III MeSH
• vaskulární endoteliální růstový faktor A MeSH

Pulmonary hypertension (PH), associated with imbalance in vasoactive mediators and massive remodeling of pulmonary vasculature, represents a serious health complication. Despite the progress in treatment, PH patients typically have poor prognoses with severely affected quality of life. Asymmetric dimethyl arginine (ADMA), endogenous inhibitor of endothelial nitric oxide synthase (eNOS), also represents one of the critical regulators of pulmonary vascular functions. The present study describes a novel mechanism of ADMA-induced dysfunction in human pulmonary endothelial and smooth muscle cells. The effect of ADMA was compared with well-established model of hypoxia-induced pulmonary vascular dysfunction. It was discovered for the first time that ADMA induced the activation of signal transducer and activator of transcription 3 (STAT3) and stabilization of hypoxia inducible factor 1α (HIF-1α) in both types of cells, associated with drastic alternations in normal cellular functions (e.g., nitric oxide production, cell proliferation/Ca(2+) concentration, production of pro-inflammatory mediators, and expression of eNOS, DDAH1, and ICAM-1). Additionally, ADMA significantly enhanced the hypoxia-mediated increase in the signaling cascades. In summary, increased ADMA may lead to manifestation of PH phenotype in human endothelial and smooth muscle cells via the STAT3/HIF-1α cascade. Therefore this signaling pathway represents the potential pathway for future clinical interventions in PH.

• Klíčová slova
• Asymmetric dimethyl arginine, Human pulmonary artery endothelial cell, Human pulmonary artery smooth muscle cell, Hypoxia, Pulmonary hypertension,
• MeSH
• amidohydrolasy metabolismus   MeSH
• arginin analogy a deriváty   farmakologie   MeSH
• arteria pulmonalis účinky léků   metabolismus   patofyziologie   MeSH
• endoteliální buňky účinky léků   metabolismus   MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa metabolismus   MeSH
• hypoxie buňky MeSH
• kultivované buňky MeSH
• lidé MeSH
• mediátory zánětu metabolismus   MeSH
• mezibuněčná adhezivní molekula-1 metabolismus   MeSH
• myocyty hladké svaloviny účinky léků   metabolismus   MeSH
• oxid dusnatý metabolismus   MeSH
• plicní hypertenze etiologie   metabolismus   patofyziologie   MeSH
• proliferace buněk účinky léků   MeSH
• signální transdukce účinky léků   MeSH
• svaly hladké cévní účinky léků   metabolismus   patofyziologie   MeSH
• synthasa oxidu dusnatého, typ III metabolismus   MeSH
• transkripční faktor STAT3 metabolismus   MeSH
• vápník metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• amidohydrolasy MeSH
• arginin MeSH
• dimethylargininase MeSH Prohlížeč
• faktor 1 indukovatelný hypoxií - podjednotka alfa MeSH
• HIF1A protein, human MeSH Prohlížeč
• ICAM1 protein, human MeSH Prohlížeč
• mediátory zánětu MeSH
• mezibuněčná adhezivní molekula-1 MeSH
• N,N-dimethylarginine MeSH Prohlížeč
• NOS3 protein, human MeSH Prohlížeč
• oxid dusnatý MeSH
• STAT3 protein, human MeSH Prohlížeč
• synthasa oxidu dusnatého, typ III MeSH
• transkripční faktor STAT3 MeSH
• vápník MeSH

BACKGROUND/AIMS: Complex interplay of genetic and (patho)physiological factors influence availability of nitric oxide during the development and progression of diabetic complications. We assessed predictive value of commonly studied methylated asymmetric and symmetric dimethylarginines (ADMA and SDMA) and selected single nucleotide polymorphisms (SNPs) in dimethylarginine dimethylaminohydrolase (DDAH) 1 and 2 genes for the progression of diabetic nephropathy (DN). METHODS: A total of 341 type 1 and type 2 diabetes patients with variable degree of kidney disease were included at baseline. Plasma levels of ADMA, SDMA and L-arginine were measured and six tagging SNPs in DDAH1 and 2 were determined. Progression of DN was defined as a transition from any given stage to a more advanced stage of albuminuria. Competing risk analysis was applied. RESULTS: Plasma levels of ADMA and SDMA significantly correlated with GFR. No significant genotype-phenotype relationship was ascertained for ADMA and DDAH variants, but SNP rs805304 exhibited marginally significant association with DN. ADMA, SDMA and L-arginine/ADMA ratio standardised to GFR were identified as significant predictors of DN progression but not GFR decline using multivariate competing risk analysis. CONCLUSIONS: In our study we confirmed potentially significant role of ADMA and SDMA for the assessment of risk of DN progression in European diabetic population.

• MeSH
• amidohydrolasy genetika   MeSH
• arginin analogy a deriváty   krev   genetika   MeSH
• diabetes mellitus 1. typu komplikace   MeSH
• diabetes mellitus 2. typu komplikace   MeSH
• diabetické nefropatie * krev   etiologie   genetika   MeSH
• dospělí MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metylace MeSH
• multivariační analýza MeSH
• následné studie MeSH
• prediktivní hodnota testů MeSH
• prognóza MeSH
• progrese nemoci * MeSH
• průřezové studie MeSH
• reprodukovatelnost výsledků MeSH
• rizikové faktory MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• amidohydrolasy MeSH
• arginin MeSH
• dimethylargininase MeSH Prohlížeč
• N,N-dimethylarginine MeSH Prohlížeč
• symmetric dimethylarginine MeSH Prohlížeč

Human MDA-MB-231 derived breast cancer cell lines 1833 and 4175 have different metastatic potentials in terms of their tissue tropisms and aggressiveness. Cell line 1833 is specifically metastatic to the bone. The highly aggressive cell line 4175 is specific to the lung. We performed 2-DE analysis of the cell lines. We found 16 significantly changed protein spots, 14 protein spots were identified. Expression of cathepsin D, triosephosphate isomerase, phosphoglycerate kinase 1, heme binding protein 1 and annexin 2 could be correlated with the in vitro aggressiveness of the respective cell lines. Interstitial collagenase and dimethylargininase 2 were exclusive to the cell line 1833 and might contribute to its bone specificity. Serpin B9, cathepsin B chain b, galectin 3 and HSP 27 were changed in the lung specific cell line 4175. The possible contribution of identified proteins to differences in metastatic behavior of the cell lines is discussed.

• MeSH
• 2D gelová elektroforéza metody   MeSH
• hmotnostní spektrometrie metody   MeSH
• invazivní růst nádoru MeSH
• kathepsin D biosyntéza   MeSH
• kolagenasy biosyntéza   MeSH
• koncentrace vodíkových iontů MeSH
• lidé MeSH
• metastázy nádorů MeSH
• nádorové buněčné linie MeSH
• nádory prsu metabolismus   patologie   MeSH
• peptidy chemie   MeSH
• počítačové zpracování obrazu MeSH
• regulace genové exprese u nádorů * MeSH
• stanovení celkové genové exprese MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• kathepsin D MeSH
• kolagenasy MeSH
• peptidy MeSH