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Background: Circulating progenitor cells (CPC) contribute to the homeostasis of the vessel wall, and a reduced CPC count predicts cardiovascular morbidity and mortality. We tested the hypothesis that CPC count improves cardiovascular risk stratification and that this is modulated by low-grade inflammation. Methodology/Principal Findings: We pooled data from 4 longitudinal studies, including a total of 1,057 patients having CPC determined and major adverse cardiovascular events (MACE) collected. We recorded cardiovascular risk factors and high-sensitive C-reactive protein (hsCRP) level. Risk estimates were derived from Cox proportional hazard analyses. CPC count and/or hsCRP level were added to a reference model including age, sex, cardiovascular risk factors, prevalent CVD, chronic renal failure (CRF) and medications. The sample was composed of high-risk individuals, as 76.3% had prevalent CVD and 31.6% had CRF. There were 331 (31.3%) incident MACE during an average 1.7±1.1 year follow-up time. CPC count was independently associated with incident MACE even after correction for hsCRP. According to C-statistics, models including CPC yielded a non-significant improvement in accuracy of MACE prediction. However, the integrated discrimination improvement index (IDI) showed better performance of models including CPC compared to the reference model and models including hsCRP in identifying MACE. CPC count also yielded significant net reclassification improvements (NRI) for CV death, non-fatal AMI and other CV events. The effect of CPC was independent of hsCRP, but there was a significant more-than-additive interaction between low CPC count and raised hsCRP level in predicting incident MACE. Conclusions/Significance: In high risk individuals, a reduced CPC count helps identifying more patients at higher risk of MACE over the short term, especially in combination with a raised hsCRP level.
Background: Adaptation to low oxygen by changing gene expression is vitally important for cell survival and tissue development. The sprouting of new blood vessels, initiated from endothelial cells, restores the oxygen supply of ischemic tissues. In contrast to the transcriptional response induced by hypoxia, which is mainly mediated by members of the HIF family, there are only few studies investigating alternative splicing events. Therefore, we performed an exon array for the genome-wide analysis of hypoxia-related changes of alternative splicing in endothelial cells.
Methodology/Principal findings: Human umbilical vein endothelial cells (HUVECs) were incubated under hypoxic conditions (1% O(2)) for 48 h. Genome-wide transcript and exon expression levels were assessed using the Affymetrix GeneChip Human Exon 1.0 ST Array. We found altered expression of 294 genes after hypoxia treatment. Upregulated genes are highly enriched in glucose metabolism and angiogenesis related processes, whereas downregulated genes are mainly connected to cell cycle and DNA repair. Thus, gene expression patterns recapitulate known adaptations to low oxygen supply. Alternative splicing events, until now not related to hypoxia, are shown for nine genes: six which are implicated in angiogenesis-mediated cytoskeleton remodeling (cask, itsn1, larp6, sptan1, tpm1 and robo1); one, which is involved in the synthesis of membrane-anchors (pign) and two universal regulators of gene expression (cugbp1 and max).
Conclusions/Significance: For the first time, this study investigates changes in splicing in the physiological response to hypoxia on a genome-wide scale. Nine alternative splicing events, until now not related to hypoxia, are reported, considerably expanding the information on splicing changes due to low oxygen supply. Therefore, this study provides further knowledge on hypoxia induced gene expression changes and presents new starting points to study the hypoxia adaptation of endothelial cells.
Aging is a complex process that is linked to an increased incidence of major diseases such as cardiovascular and neurodegenerative disease, but also cancer and immune disorders. MicroRNAs (miRNAs) are small non-coding RNAs, which post-transcriptionally control gene expression by inhibiting translation or inducing degradation of targeted mRNAs. MiRNAs target up to hundreds of mRNAs, thereby modulating gene expression patterns. Many miRNAs appear to be dysregulated during cellular senescence, aging and disease. However, only few miRNAs have been so far linked to age-related changes in cellular and organ functions. The present article will discuss these findings, specifically focusing on the cardiovascular and neurological systems.
ANGIOGENES : knowledge database for protein-coding and noncoding RNA genes in endothelial cells
(2016)
Increasing evidence indicates the presence of long noncoding RNAs (lncRNAs) is specific to various cell types. Although lncRNAs are speculated to be more numerous than protein-coding genes, the annotations of lncRNAs remain primitive due to the lack of well-structured schemes for their identification and description. Here, we introduce a new knowledge database “ANGIOGENES” (http://angiogenes.uni-frankfurt.de) to allow for in silico screening of protein-coding genes and lncRNAs expressed in various types of endothelial cells, which are present in all tissues. Using the latest annotations of protein-coding genes and lncRNAs, publicly-available RNA-seq data was analyzed to identify transcripts that are expressed in endothelial cells of human, mouse and zebrafish. The analyzed data were incorporated into ANGIOGENES to provide a one-stop-shop for transcriptomics data to facilitate further biological validation. ANGIOGENES is an intuitive and easy-to-use database to allow in silico screening of expressed, enriched and/or specific endothelial transcripts under various conditions. We anticipate that ANGIOGENES serves as a starting point for functional studies to elucidate the roles of protein-coding genes and lncRNAs in angiogenesis.
These are exciting times for translational medicine as the convergence between fundamental and clinical research comes of age. The new EMBO Press publishing platform reinforces the standing of EMBO Molecular Medicine as the journal that matches high quality, novel research with rigorous editorial and ethical standards. It will also cement the journal's global reach and relevance - whether in highly active fields or explorative forays into emerging areas.
1993 stellte die Entdeckung winziger Stückchen von Ribonukleinsäuren, heute als microRNAs bekannt, die Wissenschaftler vor ein Rätsel. Erstmals beobachtet wurden sie in dem Fadenwurm C. elegans, einem einfachen, vergleichsweise leicht durchschaubaren Organismus. Was die Wissenschaftler verwirrte, war die Tatsache, dass diese microRNAs ganz offensichtlich nicht für Proteine kodierten. Welche Funktion haben sie dann? Inzwischen weiß man, dass sie eine wichtige Rolle bei der Genregulation spielen. Und das nicht nur im Fadenwurm: MicroRNAs sind evolutionär hoch konserviert, sie kommen auch in höheren Organismen vor. Im Menschen sind mehr als 1500 microRNAs beschrieben, und man geht davon aus, dass mindestens 30 Prozent der Gene direkt durch microRNAs reguliert werden. Das lässt sich auch für therapeutische Zwecke nutzen. In unserer Arbeitsgruppe erforschen wir insbesondere die Rolle der microRNAs bei Herz- und Gefäß-Erkrankungen.
In einem Wurm wurden sie 1993 zuerst entdeckt: kleine Ribonukleinsäuren (microRNAs), die nicht für ein Protein kodieren, sondern gezielt mit Boten-RNA (mRNA) paaren. Damit stoppen sie die Übersetzung der mRNA in Protein (Translation) oder lösen den Abbau der Ziel-mRNA aus. In den folgenden Jahren wurde deutlich, dass microRNAs auch beim Menschen eine wichtige Rolle spielen. Möglicherweise ist jedes dritte oder vierte Gen durch microRNA reguliert. Nur zwei bis drei Prozent des humanen Genoms kodiert Proteine; die Mehrzahl der gebildeten RNAs (über 80 Prozent) haben unbekannte oder regulatorische Funktionen. ...
Bone marrow and plasma FGF‐23 in heart failure patients : novel insights into the heart–bone axis
(2019)
Aims: Fibroblast growth factor 23 (FGF‐23) is known to be elevated in patients with congestive heart failure (CHF). As FGF‐23 is expressed in the bone but can also be expressed in the myocardium, the origin of serum FGF‐23 in CHF remains unclear. It is also unclear if FGF‐23 expressed in the bone is associated with outcome in CHF. The aim of the present study was to investigate FGF‐23 levels measured in bone marrow plasma (FGF‐23‐BM) and in peripheral blood (FGF‐23‐P) in CHF patients to gain further insights into the heart–bone axis of FGF‐23 expression. We also investigated possible associations between FGF‐23‐BM as well as FGF‐23‐P and outcome in CHF patients.
Methods and results: We determined FGF‐23‐P and FGF‐23‐BM levels in 203 CHF patients (85% male, mean age 61.3 years) with a left ventricular ejection fraction (LVEF) ≤45% and compared them with those of 48 healthy controls (48% male, mean age 39.2 years). We investigated the association between FGF‐23‐BM and FGF‐23‐P with all‐cause mortality in CHF patients, 32 events, median follow‐up 1673 days, interquartile range [923, 1828]. FGF‐23‐P (median 60.3 vs. 22.0 RU/mL, P < 0.001) and FGF‐23‐BM (median 130.7 vs. 93.1 RU/mL, P < 0.001) levels were higher in CHF patients compared with healthy controls. FGF‐23‐BM levels were significantly higher than FGF‐23‐P levels in both CHF patients and in healthy controls (P < 0.001). FGF‐23‐P and FGF‐23‐BM correlated significantly with LVEF (r = −0.37 and r = −0.33, respectively), N terminal pro brain natriuretic peptide levels (r = 0.57 and r = 0.6, respectively), New York Heart Association status (r = 0.28 and r = 0.25, respectively), and estimated glomerular filtration rate (r = −0.43 and r = −0.41, respectively) (P for all <0.001) and were independently associated with all‐cause mortality in CHF patients after adjustment for LVEF, estimated glomerular filtration rate, New York Heart Association status, and N terminal pro brain natriuretic peptide, hazard ratio 2.71 [confidence interval: 1.18–6.20], P = 0.018, and hazard ratio 2.80 [confidence interval: 1.19–6.57], P = 0.018, respectively.
Conclusions: In CHF patients, FGF‐23 is elevated in bone marrow plasma and is independently associated with heart failure severity and all‐cause mortality. The failing heart seems to interact via FGF‐23 within a heart–bone axis.