1,720,959 research outputs found
Stem Cells in Cardiovascular Medicine: Historical Overview and Future Prospects
No full textCardiovascular diseases remain the leading cause of death in the developed world, accounting for more than 30% of all deaths. In a large proportion of these patients, acute myocardial infarction is usually the first manifestation, which might further progress to heart failure. In addition, the human heart displays a low regenerative capacity, leading to a loss of cardiomyocytes and persistent tissue scaring, which entails a morbid pathologic sequela. Novel therapeutic approaches are urgently needed. Stem cells, such as induced pluripotent stem cells or embryonic stem cells, exhibit great potential for cell-replacement therapy and an excellent tool for disease modeling, as well as pharmaceutical screening of novel drugs and their cardiac side effects. This review article covers not only the origin of stem cells but tries to summarize their translational potential, as well as potential risks and clinical translation
Dysregulation of Krüppel-like Factor 2 and Myocyte Enhancer Factor 2D Drive Cardiac Microvascular Inflammation and Dysfunction in Diabetes
No full textCardiovascular complications are the main cause of morbidity and mortality from diabetes. Herein, vascular inflammation is a major pathological manifestation. We previously characterized the cardiac microvascular inflammatory phenotype in diabetic patients and highlighted micro-RNA 92a (miR-92a) as a driver of endothelial dysfunction. In this article, we further dissect the molecular underlying of these findings by addressing anti-inflammatory Krüppel-like factors 2 and 4 (KLF2 and KLF4). We show that KLF2 dysregulation in diabetes correlates with greater monocyte adhesion as well as migratory defects in cardiac microvascular endothelial cells. We also describe, for the first time, a role for myocyte enhancer factor 2D (MEF2D) in cardiac microvascular dysfunction in diabetes. We show that both KLFs 2 and 4, as well as MEF2D, are dysregulated in human and porcine models of diabetes. Furthermore, we prove a direct interaction between miR-92a and all three targets. Altogether, our data strongly qualify miR-92a as a potential therapeutic target for diabetes-associated cardiovascular disease
Correction: Samak et al. Dysregulation of Krüppel-like Factor 2 and Myocyte Enhancer Factor 2D Drive Cardiac Microvascular Inflammation and Dysfunction in Diabetes. Int. J. Mol. Sci. 2023, 24, 2482
No full textIn the original publication [...
Micro-RNA 92a as a Therapeutic Target for Cardiac Microvascular Dysfunction in Diabetes
Full text linkMicrovascular dysfunction is a pathological hallmark of diabetes, and is central to the ethology of diabetes-associated cardiac events. Herein, previous studies have highlighted the role of the vasoactive micro-RNA 92a (miR-92a) in small, as well as large, animal models. In this study, we explore the effects of miR-92a on mouse and human cardiac microvascular endothelial cells (MCMEC, HCMEC), and its underlying molecular mechanisms. Diabetic HCMEC displayed impaired angiogenesis and a pronounced inflammatory phenotype. Quantitative PCR (qPCR) showed an upregulation of miR-92a in primary diabetic HCMEC. Downregulation of miR-92a by antagomir transfection in diabetic HCMEC rescued angiogenesis and ameliorated diabetic endothelial bed inflammation. Furthermore, additional analysis of potential in silico-identified miR-92a targets in diabetic HCMEC revealed the miR-92a dependent downregulation of an essential metalloprotease, ADAM10. Accordingly, downregulation of ADAM10 impaired angiogenesis and wound healing in MCMEC. In myocardial tissue slices from diabetic pigs, ADAM10 dysregulation in micro- and macro-vasculature could be shown. Altogether, our data demonstrate the role of miR-92a in cardiac microvascular dysfunction and inflammation in diabetes. Moreover, we describe for the first time the metalloprotease ADAM10 as a novel miR-92a target, mediating its anti-angiogenic effect
Single-cell transcriptomics reveal extracellular vesicles secretion with a cardiomyocyte proteostasis signature during pathological remodeling
No full textAbstract Aberrant Wnt activation has been reported in failing cardiomyocytes. Here we present single cell transcriptome profiling of hearts with inducible cardiomyocyte-specific Wnt activation (β-cat Δex3 ) as well as with compensatory and failing hypertrophic remodeling. We show that functional enrichment analysis points to an involvement of extracellular vesicles (EVs) related processes in hearts of β-cat Δex3 mice. A proteomic analysis of in vivo cardiac derived EVs from β-cat Δex3 hearts has identified differentially enriched proteins involving 20 S proteasome constitutes, protein quality control (PQC), chaperones and associated cardiac proteins including α-Crystallin B (CRYAB) and sarcomeric components. The hypertrophic model confirms that cardiomyocytes reacted with an acute early transcriptional upregulation of exosome biogenesis processes and chaperones transcripts including CRYAB, which is ameliorated in advanced remodeling. Finally, human induced pluripotent stem cells (iPSC)-derived cardiomyocytes subjected to pharmacological Wnt activation recapitulated the increased expression of exosomal markers, CRYAB accumulation and increased PQC signaling. These findings reveal that secretion of EVs with a proteostasis signature contributes to early patho-physiological adaptation of cardiomyocytes, which may serve as a read-out of disease progression and can be used for monitoring cellular remodeling in vivo with a possible diagnostic and prognostic role in the future.Open-Access-Publikationsfonds 202
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Micro-RNA 92a as a therapeutic target for cardiac microvascular dysfunction in diabetes
No full textDie mikrovaskuläre Dysfunktion ist ein pathologisches Merkmal des diabetischen Myokards und spielt eine zentrale Rolle bei der Ätiologie von Diabetes-assoziierten Herzerkrankungen. Frühere Studien haben die Rolle der vasoaktiven Mikro-RNA 92a (miR-92a) sowohl in kleinen als auch in großen Tiermodellen aufgezeigt. In dieser Studie wurden die Auswirkungen von miR-92a in primären humanen kardialen mikrovaskulären Endothelzellen (HCMEC) und ihren Gegenstücken aus der Maus (MCMEC) untersucht. Ich habe die endotheliale Dysfunktion und Entzündung in HCMEC von Diabetikern charakterisiert und ihre Hochregulierung von miR-92a beschrieben. Außerdem konnte ich zeigen, dass die Hemmung von miR-92a in diabetischen HCMEC die Angiogenese unterstützte und die Entzündung des Endothelbetts verringerte. Die in silico-Analyse identifizierte vier konservierte Zielmoleküle, die miR-92a nachgeschaltet sind und einen direkten Bezug zu den beobachteten Phänotypen haben. Neu ist, dass ich die miR-92a-abhängige Herunterregulierung der koronaren essentiellen Metalloproteinase ADAM10 in diabetischen HCMEC nachweisen konnte. Dies konnte auch in diabetischem ventrikulärem Gewebe von Schweinen gezeigt werden. Dementsprechend beeinträchtigte die Herunterregulierung von ADAM10 die Angiogenese, Sprossung und Wundheilung in HCMEC und MCMEC. Darüber hinaus ist eine Dysregulation der entzündungshemmenden Krüppel-like Faktoren (KLF) 2 und 4 in diabetischen HCMEC und diabetischen Schweineventrikeln festgestellt worden. Tatsächlich führte die Ablation von KLF2 in nicht-diabetischen HCMEC zum gleichen Entzündungsphänotyp wie in ihren diabetischen Pendants. Upstream von KLFs wurde eine Fehlregulierung des Myozyten-Enhancer-Faktors 2D (MEF2D) in diabetischen HCMEC und Schweineventrikeln festgestellt. Mit Hilfe von dualen Luziferase-Reporter-Assays bestätigte ich eine direkte Interaktion zwischen miR-92a und allen vier Zielmolekülen. Es hat sich auch gezeigt, dass die Hemmung von miR-92a die Werte dieser Targets in diabetischen HCMEC wiederherstellt.
Insgesamt zeigen meine Ergebnisse neue molekulare Mechanismen in der Pathogenese der kardialen mikrovaskulären Dysfunktion bei Diabetes mellitus auf und qualifizieren miR-92a nachdrücklich als therapeutisches Ziel.Microvascular dysfunction is a pathological hallmark of the diabetic myocardium, and is central to the etiology of diabetes-associated cardiac events. Herein, previous studies highlighted the role of the vasoactive micro-RNA 92a (miR-92a) in small, as well as large animal models. In this study, the effects of miR-92a in primary human cardiac microvascular endothelial cells (HCMEC) and their mouse equivalents (MCMEC) were explored. I characterized endothelial dysfunction and inflammation in HCMEC from diabetic patients and reported their upregulation of miR-92a. Importantly, I could show that inhibition of miR-92a in diabetic HCMEC rescued angiogenesis and ameliorated endothelial bed inflammation. The in silico analysis identified four conserved targets downstream of miR-92a with direct relevance to the observed phenotypes. Of novelty, I reported the miR-92a-dependent downregulation of the coronary essential metalloproteinase, ADAM10, in diabetic HCMEC. This was also shown in diabetic porcine ventricular tissue. Accordingly, downregulation of ADAM10 impaired angiogenesis, sprouting and wound healing in HCMEC and MCMEC. Further, a dysregulation of the anti-inflammatory Krüppel-like factors (KLF) 2 and 4 in diabetic HCMEC and diabetic porcine left ventricles was observed. Indeed, ablation of KLF2 in non-diabetic HCMEC elicited the same inflammatory phenotype as their diabetic counterparts. Upstream of KLFs, dysregulation of myocyte enhancer factor 2D (MEF2D) in diabetic HCMEC and porcine ventricular tissue was demonstrated. By virtue of dual luciferase reporter assays, I confirmed direct interaction between miR-92a and all four targets. Importantly, inhibition of miR-92a was also shown to restore their levels in diabetic HCMEC.
Altogether, my results highlight novel molecular mechanisms in the pathogenesis of cardiac microvascular dysfunction in diabetes and strongly qualify miR-92a as a therapeutic target.2023-03-1
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