Endothelial NF-κB: the remote controller of the backyard fire in the vascular wall?

It has been established in the past few decades that the vascular endothelium, the monolayer of cells covering the inner surface of the vessel wall, functions as a master regulator to maintain the physiological integrity of vascular function and structure by actively releasing numerous vasoactive hormones that control smooth muscle cell contraction and proliferation and inflammatory cell adhesion and infiltration into the vascular wall.1 Endothelial dysfunction, which usually refers to a decrease in bioavailability of the vasoprotective nitric oxide (NO) from endothelial NO synthase (eNOS) in the presence of cardiovascular risk factors such as hypertension, hypercholesterolaemia, hyperglycaemia, and ageing, includes also other functional alterations due to pro-inflammatory, pro-coagulant, and pro-thrombotic properties and plays an important role in promoting atherosclerotic vascular disease.1 This endothelium-centric ‘inside-out’ injury paradigm of pathogenesis of vascular disease was initially proposed by Ross and Glomset in 1970s2 and has led to the important concept that modification to preserve the luminal endothelial function would protect blood

Critical Role of microRNA-21 in the Pathogenesis of Liver Diseases

MicroRNAs are small non-coding RNAs that range in length from 18 to 24 nucleotides. As one of the most extensively studied microRNAs, microRNA-21 (miR-21) is highly expressed in many mammalian cell types. It regulates multiple biological functions such as proliferation, differentiation, migration, and apoptosis. In this review, we summarized the mechanism of miR-21 in the pathogenesis of various liver diseases. While it is clear that miR-21 plays an important role in different types of liver diseases, its use as a diagnostic marker for specific liver disease or its therapeutic implication are not ready for prime time due to significant variability and heterogeneity in the expression of miR-21 in different types of liver diseases depending on the studies. Additional studies to further define miR-21 functions and its mechanism in association with each type of chronic liver diseases are needed before we can translate the bedside observations into clinical settings

Regulation of tissue factor expression: implications for coronary artery disease

Das Endothel als innerste Schicht eines Blutgefässes stellt eine Verbindung zwischen dem Blutstrom und dem Rest der Gefässwand dar. Es fungiert als eine physikalische Barriere zwischen Blut und Gefäss, dient als Quelle für Wachstumsfaktoren –und Inhibitoren sowie für Enzyme, die kardiovaskuläre Hormone sowohl aktivieren als auch deaktivieren, und ist an der Produktion von Kontraktions- bzw. Relaxations-Faktoren beteiligt. Risikofaktoren wie Daibetes, Hypertonie, Adipositas und Rauchen stören die Integrität des Endothels und führen zum Verlust der Funktionalität. Eine endotheliale Dysfunktion wird durch eine reduzierte NO Synthese gekennzeichnet, was wiederum die Aufnahme und Oxidierung zirkulierender Lipoproteine und Monozyten durch das Endothel in die Intima erleichtert. Diese vortschreitende prozess führt möglicherweise zu einer frühen arteriosklerotischen Läsion, welche sich mit der Zeit zu einer plaque mit nekrotischem Kern und fibroider Schale entwickelt, woraus im weiteren Verlauf eine plaque mit Gefahr der Ruptur entstehen kann. Die Ruptur einer instabilen Plaque ist verantwortlich für koronare Thromben, die Hauptursachen für ein akutes coronares Syndrom. Perkutane transluminale koronare Angioplastie ist ein in der Klinik routinemässig eingesetztes Verfahren zur Revaskularisierung verschlossener Gefässe. Daran angeschlossen ist die Einlage einer als Stent bezeichneten röhrenförmigen Struktur, was das wiedereröffnete Gefäss vor erneutem Verschluss bewahren soll. Stents sind gewöhnlich mit Substanzen beschichtet, welche die für eine Restenose ursächliche excessive Proliferation glatter Gefässmuskulatur unterbindet. Wie neulich gezeigt werden konnte ist, im Gegensatz zu Restenose, die Inzidenz für In-Stent-Thrombosen durch die Anwendung von sogenannten „Drug eluting stents“ nicht gesunken. Es konnte nachgewiesen werden, dass das vielfach zur Beschichtung von Stents verwendete Rapamycin die Expression von TF, Hauptinitiator der Koagulationskaskade, induziert, was ein neues Licht auf mögliche Ursachen für das Auftreten von In-Stent- Thrombosen wirft. Im ersten teil dieser Arbeit charakterisieren wir die Auswirkungen des als alternativ zu Rapamycin vorwiegend verwendeten Paclitaxel auf die TFExpresssion in menschlichen Endothelzellen. In der Tat steigert Paclitaxel die durch Thrombin induzierte endotheliale TF Protein Expression sowohl konzentrations-als auch zeitabhängig. Eine Konzentration von 10-5 mol/l erbrachte eine 2,1-fache Erhöhung in Bezug auf TF Protein und einen 1,6-fachen Anstieg der TF Oberflächenaktivität. Die Prästimulation für 1h ergab im Vergleich zu einer Vorbehandlung für 25 h keinen wesentlichen Unterschied. Anhand RT-PCR konnte gezeigt werden, dass Paclitaxel die durch Thrombin induzierte TF mRNA Expression ebenfalls erhöht. Darüber hinaus potenzierte Paclitaxel die Aktivierung der c-Jun terminalen NH2 Kinase (JNK) durch Thrombin, wohingegen die durch Thrombin vermittelte Phosphorilierung von p38 und der extrazellulären signal-regulierten Kinase (ERK) unter Zugabe von Paclitaxel unverändert blieb. Docetaxol steigerte, ähnlich dem Paclitaxel, sowohl TF Expression als auch JNK Aktivierung im Vergleich zur alleinigen Applikation von Thrombin. Der JNK Inhibitor SP600125 konnte die Thrombin-induzierte TF Expression um 35 % reduzieren. Im weiteren wurde durch SP600125 der Effekt von sowohl Paclitaxel als auch Docetaxel bezüglich TF Expression verschleiert. Schwerpunkt des zweiten Teils der Arbeit war die Untersuchung von Dimethyl Sulfoxid (DMSO) als potentielle neue Substanz zur coating von Stents. DMSO wird zur Konservierung von hämapoetischen Stammzellen verwendet und Patienten vor Knochenmarktransplantation infundiert. Trotz seiner intravenösen Anwendung wurde die Auswirkung von DMSO auf vaskuläre Zellen noch nicht untersucht. In dieser Studie konnte gezeigt werden, dass DMSO die TF Expression in menschlichen Endothelzellen, Monozyten und VSMC unterdrückt. RT-PCR zeigte die Inhibition die TF Expression auf mRNA Ebene, was durch die reduzierte Aktivierung der MAP Kinasen JNK und p38, jedoch nicht ERK, vermittelt wurde. In vivo unterdrückt DMSO die TF Aktivität und verhinderte im Maus-Modell einen thrombotischen Verschluss. Darüber hinaus inhibierte DMSO konzentrationsabhängig die Proliferation und Migration von glatten Gefässmuskelzellen, vielmehr verhinderte es die Rapamycin bzw. Paclitaxel induzierte Hochregulation der TF Expression. Da DMSO auf unterschiedlichem Gebiet der modernen Medizin bereits etabliert zur Anwendung kommt, empfehlen wir diese Substanz als neuwertiges Verfahren zur Behandlung eines Akutem Koronarsyndrom; im speziellen, DMSO scheint ein attraktives Mittel zur Beschichtung von Drug-eluting Stents zu sein, entweder allein oder in Kombination mit Rapamycin oder Paclitaxel.The innermost layer of a vessel, the endothelium, forms an interface between the circulating blood in the vascular lumen and the vessel wall. The endothelium functions as a.) a physical barrier between the blood and the vessel; b.) a vital source of enzymes activating and deactivating cardiovascular hormones; c.) a site of production of relaxing and contracting factors; and d.) a source of growth inhibitors and promoters. Risk factors such as diabetes, hypertension, obesity and smoking can disturb the integrity of the endothelium rendering it dysfunctional. A dysfunctional endothelium is characterized by a decreased endotheliumdependent relaxation which in turn facilitates the entry and oxidation of circulating lipoproteins and monocytes through the endothelium into the intima. The advancing accumulation of lipoproteins and monocytes into the intima eventually gives rise to an early atherosclerotic lesion which later develops into a necrotic core and a fibrous cap and ultimately becomes an advanced plaque at risk of rupture. Rupture of unstable plaques is responsible for coronary thrombosis, the main cause of unstable angina, acute myocardial infarction, and sudden cardiac death. Percutaneous transluminal coronary angioplasty is a clinical procedure routinely employed to revascularise occluded vessels. Following percutaneous transluminal coronary angioplasty a tube-like metal structure, a stent, is inserted into the vessel to prevent it from occluding once again. Stents are commonly coated with drugs orientated at inhibiting the excessive proliferation of vascular smooth muscle responsible for restenosis. Unlike for restenosis, recent evidence has shown that the incidence of in stent thrombosis has not decreased following the advent of drug eluting stents. Rapamycin which is widely used for coating stents has been shown to induce the expression of TF, the key initiator of the coagulation cascade. This finding shed new light on the possible causes for the occurrence of stent thrombosis. In the first part of this thesis we characterised the impact of paclitaxel, the main alternative to rapamycin, on TF expression in human endothelial cells. Indeed, paclitaxel enhanced thrombin-induced endothelial TF protein expression in a concentration- and time-dependent manner. A concentration of 10-5 mol/L elicited a 2.1-fold increase in TF protein and a 1.6-fold increase in cell surface TF activity. The effect was similar after a 1 h as compared to a 25 h pretreatment period. Real-time polymerase chain reaction revealed that paclitaxel increased thrombin-induced TF mRNA expression. Paclitaxel potently activated c-Jun terminal NH2 kinase (JNK) as compared to thrombin alone, while the thrombin-mediated phosphorylation of p38 and extracellular signal-regulated kinase remained unaffected. Similar to paclitaxel, docetaxel enhanced both TF expression and JNK activation as compared to thrombin alone. The JNK inhibitor SP600125 reduced thrombin-induced TF expression by 35%. Moreover, SP600125 blunted the effect of paclitaxel and docetaxel on thrombin-induced TF expression. Paclitaxel increases endothelial TF expression via selective activation of JNK. This observation provides novel insights into the pathogenesis of thrombus formation after paclitaxel-eluting stent deployment and may have an impact on drug-eluting stent design. In the second part of this thesis we directed our efforts at characterising the potential application of Dimethyl sulfoxide (DMSO) as a novel agent to be used for stent coating. DMSO is used for preservation of hematopoietic progenitor cells and infused into patients undergoing bone marrow transplantation. Despite of its intravenous application, the impact of DMSO on vascular cells has not been assessed. In this study we found that DMSO inhibited TF expression in human endothelial cells, monocytes, and VSMC. Real-time PCR revealed that inhibition of TF expression occurred at the mRNA level. This effect was mediated by reduced activation of the MAP kinases JNK and p38, but not ERK. In vivo, DMSO treatment suppressed TF activity and prevented thrombotic occlusion in a mouse model of carotid artery photochemical injury. DMSO also inhibited VSMC proliferation and migration in a concentration-dependent manner; moreover, it prevented rapamycin and paclitaxel-induced upregulation of TF expression. As the use of DMSO is established in different areas of modern medicine, we propose this drug as a novel strategy for treating acute coronary syndromes; in particular, DMSO seems to represent an attractive compound for application on drug-eluting stents, either alone or in combination with rapamycin or paclitaxel

Four Reasons Why There Is No “Poverty Trap” In Rural China

En 2020, China eliminó la pobreza regional general y terminó la ardua tarea de resolver el problema de la pobreza absoluta. Aunque existe un problema real persistente de pobreza relativa, el riesgo objetivo de caer en una trampa de pobreza en las regiones subdesarrolladas de China razonablemente no existe. Este artículo analiza cuatro perspectivas que sustentan tal afirmación: la institucional, la histórica, la individual y la espiritual.In 2020 China eliminated the overall regional poverty and finished the arduous task of solving the problem of absolute poverty. Even though there is an actual lingering problem of relative poverty, the objective risk of falling into a poverty trap in China’s underdeveloped regions does not reasonably exist. This article analyzes four perspectives to underpin such statement: the institutional, the historical, the individual, and the spiritual power

Perspectives of Targeting mTORC1–S6K1 in Cardiovascular Aging

The global population aging is accelerating and age-associated diseases including cardiovascular diseases become more challenging. The underlying mechanisms of aging and age-associated cardiovascular dysfunction remain elusive. There are substantial evidences demonstrating a pivotal role of the mammalian target of rapamycin complex 1 (mTORC1) and its down-stream effector S6K1 signaling in mammalian lifespan regulation and age-related diseases such as type II diabetes mellitus and cancer. The role of mTORC1–S6K1 in age-related cardiovascular diseases is, however, largely unknown and the available experimental results are controversial. This review article primarily summarizes the most recent advances toward understanding the role of mTORC1–S6K1 in cardiovascular aging and discusses the future perspectives of targeting mTORC1–S6K1 signaling as a healthy lifespan extension modality in anti-aging and anti-cardiovascular aging

Metabolomics analysis revealed distinct cyclic changes of metabolites altered by chronic ethanol-plus-binge and Shp-deficiency

Background Chronic ethanol consumption causes alcoholic liver disease (ALD) and disruption of the circadian system facilitates the development of ALD. Small heterodimer partner (SHP) is a nuclear receptor and critical regulator of hepatic lipid metabolism. This study aims at depicting circadian metabolomes altered by chronic ethanol-plus-binge and Shp-deficiency using high throughput Metabolomics. Methods Wild-type (WT) C57Bl/6 and Shp-/- mice were fed the control diet (CD) or Lieber De-Carli ethanol liquid diet (ED) for 10 days followed by a single bout of maltose (CD+M) or ethanol (ED+E) binge on the 11th day. Serum and liver were collected over a 24 hr light-dark (LD) cycle at Zeitgeber time ZT12, ZT18, ZT0 and ZT6 and metabolomics was performed using GC-MS. Results A total of 110 metabolites were identified in liver and of those 80 were also present in serum from pathways of carbohydrates, lipids, pentose phosphate, amino acids, nucleotides and tricarboxylic acid (TCA) cycle. In the liver, 91% of metabolites displayed rhythmicity with ED+E whereas in the serum, only 87% were rhythmic. Bioinformatics analysis identified unique metabolome patterns altered in WT CD+M, WT ED+E, Shp-/- CD+M, and Shp-/- ED+E groups. Specifically, metabolites from the nucleotide and amino acid pathway (ribose, glucose-6-phosphate, glutamic acid, aspartic acid and seduheptulose-7-P) were elevated in Shp-/- CD+M mice during the dark cycle, whereas metabolites including N-methylalanine, 2-hydroxybutyric acid, 2-hydroxyglutarate were elevated in WT ED+E mice during the light cycle. The rhythmicity and abundance of other individual metabolites were also significantly altered by both control and ethanol diets. Conclusions Metabolomics provides a useful means to identify unique metabolites altered by chronic ethanol-plus-binge

H19 potentiates let-7 family expression through reducing PTBP1 binding to their precursors in cholestasis

Cholestasis induces the hepatic long non-coding RNA H19, which promotes the progression of cholestatic liver fibrosis. However, microRNAs that are dysregulated by H19 during cholestasis remain elusive. Using miRNA-sequencing analysis followed by qPCR validation, we identified marked upregulation of eight members of the let-7 family in cholestatic livers by bile duct ligation (BDL) and H19 overexpression. In particular, the expression of let-7a-1/7d/7f-1 was highly induced in H19-BDL livers but decreased in H19KO-BDL livers. Interestingly, H19 decreased the nuclear let-7 precursors as well as the primary transcripts of let-7a-1/7d/7f-1 levels in BDL mouse livers. Bioinformatics, RNA pull-down, and RNA immunoprecipitation (RIP) assays revealed that the crucial RNA-binding protein polypyrimidine tract-binding protein 1 (PTBP1), an H19 interaction partner, interacted with the precursors of let-7a-1 and let-7d and suppressed their maturation. Both PTBP1 and let-7 expression was differentially regulated by different bile acid species in hepatocyte and cholangiocyte cells. Further, H19 negatively regulated PTBP1's mRNA and protein levels but did not affect its subcellular distribution in BDL mouse livers. Moreover, we found that H19 restrained but PTBP1 facilitated the bioavailability of let-7 miRNAs to their targets. Taken together, this study revealed for the first time that H19 promoted let-7 expression by decreasing PTBP1's expression level and its binding to the let-7 precursors in cholestasis