According to the World Health Organization, cardiovascular diseases are the main cause of death worldwide. They may be caused by various factors or combinations of factors. Frequently, endothelial dysfunction is involved in either development of the disorder or results from it. On the other hand, the endothelium may be disordered for other reasons, e.g., due to infection, such as COVID-19. The understanding of the role and significance of the endothelium in the body has changed significantly over time-from a simple physical barrier to a complex system encompassing local and systemic regulation of numerous processes in the body. Endothelium disorders may arise from impairment of one or more signaling pathways affecting dilator or constrictor activity, including nitric oxide-cyclic guanosine monophosphate activation, prostacyclin-cyclic adenosine monophosphate activation, phosphodiesterase inhibition, and potassium channel activation or intracellular calcium level inhibition. In this review, plants are summarized as sources of biologically active substances affecting the endothelium. This paper compares individual substances and mechanisms that are known to affect the endothelium, and which subsequently may cause the development of cardiovascular disorders.

• MeSH
• cévní endotel cytologie   účinky léků   fyziologie   MeSH
• lidé MeSH
• rostlinné extrakty chemie   farmakologie   MeSH
• rostliny chemie   metabolismus   MeSH
• sekundární metabolismus * MeSH
• vazodilatace účinky léků   fyziologie   MeSH
• vazodilatancia chemie   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Obesity would result in increased cardiovascular morbidity including endothelial destruction, and miRNAs are recognized as potent regulators on endothelial function. We therefore explored pivotal miRNAs before and after exercise and dietary intervention in obese adults and examined their potential relationships with selected endothelial function and biomarkers. Obese adults were included in an exercise and dietary intervention training program for 2 months. At the beginning and the end, measurements of anthropometric and metabolic parameters were performed. Flow-mediated dilation, endothelial related biochemicals and circulating miR-214 and miR-126 levels were also determined. Results showed that circulating miR-214 and miR-126 levels were significantly enhanced (P < 0.05) by exercise and dietary intervention along with improved endothelial function. The relationship between relative changes of miR-214 and that of endothelial progenitor cells was significant (r = 0.589, P < 0.05); relative expression of miR-126 was also significantly (r = 0.433, P < 0.05) correlated with endothelial nitric oxide synthase. The intervention lead to upregulation of circulating miR-214 and miR-126 in obesity, and these molecular adaptations are associated with improved endothelial function during the restoring process.

• MeSH
• cévní endotel cytologie   metabolismus   MeSH
• dospělí MeSH
• endoteliální progenitorové buňky cytologie   MeSH
• lidé MeSH
• mikro RNA krev   MeSH
• obezita * diagnóza   dietoterapie   metabolismus   MeSH
• polymerázová řetězová reakce s reverzní transkripcí metody   MeSH
• tělesná námaha MeSH
• terapie cvičením metody   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH

SCOPE: Aberrant vascular smooth muscle cell (VSMC) proliferation is involved in atherosclerotic plaque formation and restenosis. Mediterranean spices have been reported to confer cardioprotection, but their direct influence on VSMCs has largely not been investigated. This study aims at examining rosmarinic acid (RA) and 11 related constituents for inhibition of VSMC proliferation in vitro, and at characterizing the most promising compound for their mode of action and influence on neointima formation in vivo. METHODS AND RESULTS: RA, rosmarinic acid methyl ester (RAME), and caffeic acid methyl ester inhibit VSMC proliferation in a resazurin conversion assay with IC50 s of 5.79, 3.12, and 6.78 µm, respectively. RAME significantly reduced neointima formation in vivo in a mouse femoral artery cuff model. Accordingly, RAME leads to an accumulation of VSMCs in the G0 /G1 cell-cycle phase, as indicated by blunted retinoblastoma protein phosphorylation upon mitogen stimulation and inhibition of cyclin-dependent kinase 2 in vitro. CONCLUSION: RAME represses PDGF-induced VSMC proliferation in vitro and reduces neointima formation in vivo. These results recommend RAME as an interesting compound with VSMC-inhibiting potential. Future metabolism and pharmacokinetics studies might help to further evaluate the potential relevance of RAME and other spice-derived polyphenolics for vasoprotection.

• MeSH
• cévní endotel cytologie   účinky léků   patologie   MeSH
• cinnamáty aplikace a dávkování   škodlivé účinky   farmakologie   terapeutické užití   MeSH
• depsidy aplikace a dávkování   škodlivé účinky   farmakologie   terapeutické užití   MeSH
• endoteliální buňky pupečníkové žíly (lidské) cytologie   MeSH
• fosforylace účinky léků   MeSH
• kardiovaskulární látky škodlivé účinky   farmakologie   terapeutické užití   MeSH
• koření analýza   MeSH
• krysa rodu rattus MeSH
• kultivované buňky MeSH
• lidé MeSH
• metylace MeSH
• myši inbrední C57BL MeSH
• náhodné rozdělení MeSH
• patologická angiogeneze metabolismus   patologie   prevence a kontrola   MeSH
• posttranslační úpravy proteinů účinky léků   MeSH
• proliferace buněk účinky léků   MeSH
• retinoblastomový protein metabolismus   MeSH
• rozmarýn chemie   růst a vývoj   MeSH
• strava středomořská MeSH
• svaly hladké cévní cytologie   účinky léků   metabolismus   patologie   MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Středomoří MeSH

BACKGROUND: An emerging metabolic theory of pulmonary hypertension (PH) suggests that cellular and mitochondrial metabolic dysfunction underlies the pathology of this disease. We and others have previously demonstrated the existence of hyperproliferative, apoptosis-resistant, proinflammatory adventitial fibroblasts from human and bovine hypertensive pulmonary arterial walls (PH-Fibs) that exhibit constitutive reprogramming of glycolytic and mitochondrial metabolism, accompanied by an increased ratio of glucose catabolism through glycolysis versus the tricarboxylic acid cycle. However, the mechanisms responsible for these metabolic alterations in PH-Fibs remain unknown. We hypothesized that in PH-Fibs microRNA-124 (miR-124) regulates PTBP1 (polypyrimidine tract binding protein 1) expression to control alternative splicing of pyruvate kinase muscle (PKM) isoforms 1 and 2, resulting in an increased PKM2/PKM1 ratio, which promotes glycolysis and proliferation even in aerobic environments. METHODS: Pulmonary adventitial fibroblasts were isolated from calves and humans with severe PH (PH-Fibs) and from normal subjects. PTBP1 gene knockdown was achieved via PTBP1-siRNA; restoration of miR-124 was performed with miR-124 mimic. TEPP-46 and shikonin were used to manipulate PKM2 glycolytic function. Histone deacetylase inhibitors were used to treat cells. Metabolic products were determined by mass spectrometry-based metabolomics analyses, and mitochondrial function was analyzed by confocal microscopy and spectrofluorometry. RESULTS: We detected an increased PKM2/PKM1 ratio in PH-Fibs compared with normal subjects. PKM2 inhibition reversed the glycolytic status of PH-Fibs, decreased their cell proliferation, and attenuated macrophage interleukin-1β expression. Furthermore, normalizing the PKM2/PKM1 ratio in PH-Fibs by miR-124 overexpression or PTBP1 knockdown reversed the glycolytic phenotype (decreased the production of glycolytic intermediates and byproducts, ie, lactate), rescued mitochondrial reprogramming, and decreased cell proliferation. Pharmacological manipulation of PKM2 activity with TEPP-46 and shikonin or treatment with histone deacetylase inhibitors produced similar results. CONCLUSIONS: In PH, miR-124, through the alternative splicing factor PTBP1, regulates the PKM2/PKM1 ratio, the overall metabolic, proliferative, and inflammatory state of cells. This PH phenotype can be rescued with interventions at various levels of the metabolic cascade. These findings suggest a more integrated view of vascular cell metabolism, which may open unique therapeutic prospects in targeting the dynamic glycolytic and mitochondrial interactions and between mesenchymal inflammatory cells in PH.

• MeSH
• alternativní sestřih MeSH
• antagomiry metabolismus   MeSH
• cévní endotel cytologie   MeSH
• fibroblasty cytologie   účinky léků   metabolismus   MeSH
• glykolýza MeSH
• heterogenní jaderné ribonukleoproteiny antagonisté a inhibitory   genetika   metabolismus   MeSH
• inhibitory histondeacetylas farmakologie   MeSH
• interleukin-1beta metabolismus   MeSH
• lidé MeSH
• makrofágy cytologie   imunologie   metabolismus   MeSH
• mikro RNA antagonisté a inhibitory   genetika   metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• naftochinony farmakologie   MeSH
• plicní hypertenze metabolismus   patologie   MeSH
• proliferace buněk MeSH
• protein - isoformy antagonisté a inhibitory   genetika   metabolismus   MeSH
• protein vázající polypyrimidinové úseky RNA antagonisté a inhibitory   genetika   metabolismus   MeSH
• pyruvátkinasa antagonisté a inhibitory   genetika   metabolismus   MeSH
• RNA interference MeSH
• skot MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• skot MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Clinical and experimental studies indicate that muscarinic acetylcholine receptors are potential pharmacological targets for the treatment of neurological diseases. Although these receptors have been described in human, bovine and rat cerebral microvascular tissue, a subtype functional characterization in mouse brain endothelium is lacking. Here, we show that all muscarinic acetylcholine receptors (M1-M5) are expressed in mouse brain microvascular endothelial cells. The mRNA expression of M2, M3, and M5 correlates with their respective protein abundance, but a mismatch exists for M1 and M4 mRNA versus protein levels. Acetylcholine activates calcium transients in brain endothelium via muscarinic, but not nicotinic, receptors. Moreover, although M1 and M3 are the most abundant receptors, only a small fraction of M1 is present in the plasma membrane and functions in ACh-induced Ca2+ signaling. Bioinformatic analyses performed on eukaryotic muscarinic receptors demonstrate a high degree of conservation of the orthosteric binding site and a great variability of the allosteric site. In line with previous studies, this result indicates muscarinic acetylcholine receptors as potential pharmacological targets in future translational studies. We argue that research on drug development should especially focus on the allosteric binding sites of the M1 and M3 receptors.

• MeSH
• acetylcholin farmakologie   MeSH
• alosterické místo MeSH
• cévní endotel cytologie   metabolismus   MeSH
• endoteliální buňky účinky léků   metabolismus   MeSH
• mikrocévy metabolismus   MeSH
• mozek krevní zásobení   MeSH
• myši inbrední BALB C MeSH
• nikotinové receptory metabolismus   MeSH
• receptory muskarinové chemie   metabolismus   MeSH
• vápníková signalizace účinky léků   MeSH
• vazebná místa MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Inflammatory-mediated pathological processes in the endothelium arise as a consequence of the dysregulation of vascular homeostasis. Of particular importance are mediators produced by stimulated monocytes/macrophages inducing activation of endothelial cells (ECs). This is manifested by excessive soluble pro-inflammatory mediator production and cell surface adhesion molecule expression. Nitro-fatty acids are endogenous products of metabolic and inflammatory reactions that display immuno-regulatory potential and may represent a novel therapeutic strategy to treat inflammatory diseases. The purpose of our study was to characterize the effects of nitro-oleic acid (OA-NO2) on inflammatory responses and the endothelial-mesenchymal transition (EndMT) in ECs that is a consequence of the altered healing phase of the immune response. METHODS: The effect of OA-NO2 on inflammatory responses and EndMT was determined in murine macrophages and murine and human ECs using Western blotting, ELISA, immunostaining, and functional assays. RESULTS: OA-NO2 limited the activation of macrophages and ECs by reducing pro-inflammatory cytokine production and adhesion molecule expression through its modulation of STAT, MAPK and NF-κB-regulated signaling. OA-NO2 also decreased transforming growth factor-β-stimulated EndMT and pro-fibrotic phenotype of ECs. These effects are related to the downregulation of Smad2/3. CONCLUSIONS: The study shows the pleiotropic effect of OA-NO2 on regulating EC-macrophage interactions during the immune response and suggests a role for OA-NO2 in the regulation of vascular endothelial immune and fibrotic responses arising during chronic inflammation. GENERAL SIGNIFICANCE: These findings propose the OA-NO2 may be useful as a novel therapeutic agent for treatment of cardiovascular disorders associated with dysregulation of the endothelial immune response.

• MeSH
• cévní endotel cytologie   účinky léků   metabolismus   MeSH
• endoteliální buňky účinky léků   metabolismus   MeSH
• epitelo-mezenchymální tranzice * MeSH
• kyseliny olejové farmakologie   MeSH
• lidé MeSH
• makrofágy účinky léků   metabolismus   MeSH
• MAP kinasový signální systém MeSH
• myši MeSH
• NF-kappa B metabolismus   MeSH
• proteiny Smad metabolismus   MeSH
• transformující růstový faktor beta farmakologie   MeSH
• transkripční faktory STAT metabolismus   MeSH
• zánět metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

BACKGROUND: Continuous blood flow could have deleterious effects on endothelium and vascular health. This could have serious consequences in patients with heart failure treated with continuous flow left ventricular assist devices (LVAD). Therefore, we studied effect of LVAD on three circulating vascular biomarkers: stem cells (SC), endothelial progenitor cells (EPC) and microparticles (MP). METHODS: In 23 patients (5 women) with end-stage heart failure, SC, EPC and MP were measured before, and 3 and 6months after implantation of LVAD (HeartMate II). SC were defined using determination of surface antigen expression as mononuclear CD34+/CD45low+ cells and EPC as mononuclear CD34+/CD45low+/KDR+ cells. MP concentrations were determined by ELISA method. RESULTS: Three months after LVAD implantation numbers of SC and EPC significantly decreased (p=0.01 and p=0.001, respectively). On the contrary, between 3rd and 6th month after implantation they significantly increased (p=0.006 and p=0.003, respectively).MP did not change significantly during the study despite exerting similar trend as SC and EPC. CONCLUSIONS: Observed biphasic changes of SC and EPC might reflect two processes. First, shortly after LVAD implantation, improved tissue perfusion could lead to decrease in ischemic stimuli and ensuing decrease of SC and EPC. Second, continuous flow between 3rd and 6th month produced by LVAD could lead to increase of SC and EPC through activation of endothelium. This explanation could be supported also by similar trend in the changes of concentrations of MP.

• MeSH
• časové faktory MeSH
• cévní endotel cytologie   fyziologie   MeSH
• dospělí MeSH
• endoteliální progenitorové buňky fyziologie   MeSH
• kmenové buňky fyziologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• longitudinální studie MeSH
• mladý dospělý MeSH
• následné studie MeSH
• počet buněk trendy   MeSH
• podpůrné srdeční systémy trendy   MeSH
• prospektivní studie MeSH
• senioři MeSH
• srdeční komory * MeSH
• srdeční selhání krev   patofyziologie   terapie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH

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.

• 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

Nejzávažnější komplikací nádorových onemocnění je vznik vzdálených metastáz. K šíření do vzdálených orgánů využívají nádorové buňky často krevní cirkulaci. Vstup do krevního oběhu a průchod stěnou kapiláry do cílového sekundárního místa umožňují kolonizaci jiných orgánů a vznik život ohrožujících metastáz. Průchod stěnou cévy (transendoteliální migrace) je zásadní krok metastatické kaskády a poznání mechanizmů řídících tento proces by jistě přispělo k vytváření nových strategií pro cílenou proti‑metastatickou terapii. Existuje několik způsobů, jak studovat transendoteliální migraci v živých modelových organizmech (in vivo). Jejich výhoda je, že poskytují komplexní fyziologické mikroprostředí, jsou ale nákladné a technicky náročné. Proto se používají stále dokonalejší techniky pro sledování transendoteliální migrace in vitro. Jsou obecně dostupnější a méně náročné na vybavení, ale i v rámci metod studia transendoteliální migrace in vitro existuje značná variabilita ve složitosti provedení, požadavcích na speciální přístrojové vybavení, přesnosti simulace podmínek in vivo a v relevanci pro onkologické aplikace. Technické přístupy ke studiu transendoteliální migrace in vitro, jejich rozdělení, modifikace, výhody a nevýhody jsou předmětem tohoto přehledového článku.

The most dangerous aspect of cancer is the metastatic spread to other parts of the body. Cancer cells frequently use circulation to spread to secondary locations. By entering the blood­stream (in a process called intravasation) and by crossing the vessel walls at the metastatic sites (extravasation) tumor cells disseminate to distal organs and eventually form life‑threatening metastases. Crossing the vessel walls (transendothelial migration) is a vital step of metastatic cascade and the elucidation of mechanisms involved in transendothelial migration might inspire new strategies of targeted anti‑metastatic therapy. There are several methods to study transendothelial migration in living models (in vivo). Although they offer complex physiological microenvironment, they are expensive and technically demanding, therefore not widely used. As an alternative, sophisticated techniques to investigate transendothelial migration in vitro have been developed. They are generally more available and feasible, but there is still considerable variability in the difficulty of performance, the requirements for specialized devices, accuracy of in vivo simulation and relevance for oncological applications. The classification, various modifications, pros and cons of in vitro techniques for studying transendothelial migration are summarized in this review. Key words: transendothelial migration – extravasation – endothelial cells – metastasis – transwell system This work was supported by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101). The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers. Submitted: 3. 2. 2014 Accepted: 27. 3. 2014

• Klíčová slova
• extravazace, transwell systém, fluidní model,
• MeSH
• astrocyty cytologie   MeSH
• biotest metody   MeSH
• buněčné kultury metody   MeSH
• cévní endotel cytologie   MeSH
• endoteliální buňky cytologie   MeSH
• kultivované buňky MeSH
• lidé MeSH
• metastázy nádorů * MeSH
• mikrofluidní analytické techniky * MeSH
• molekulární zobrazování MeSH
• monocyty cytologie   MeSH
• nádory metabolismus   patologie   MeSH
• transendoteliální a transepiteliální migrace * fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

• Klíčová slova
• bafilomycin A1, toxicita, uhlíkové nanotuby,
• MeSH
• autofagie účinky léků   MeSH
• cévní endotel cytologie   sekrece   MeSH
• endoteliální buňky pupečníkové žíly (lidské) MeSH
• endoteliální buňky klasifikace   patologie   MeSH
• hematoencefalická bariéra MeSH
• lidé MeSH
• makrolidy aplikace a dávkování   MeSH
• myši MeSH
• nádorové buněčné linie účinky léků   MeSH
• nanočástice * toxicita   využití   MeSH
• nanotrubičky uhlíkové MeSH
• neurony cytologie   MeSH
• proliferace buněk účinky léků   MeSH
• prospektivní studie MeSH
• techniky in vitro MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH