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Article ; Online: Malat1 deficiency prevents neonatal heart regeneration by inducing cardiomyocyte binucleation.

Aslan, Galip S / Jaé, Nicolas / Manavski, Yosif / Fouani, Youssef / Shumliakivska, Mariana / Kettenhausen, Lisa / Kirchhof, Luisa / Günther, Stefan / Fischer, Ariane / Luxán, Guillermo / Dimmeler, Stefanie

JCI insight

2023 Volume 8, Issue 5

Abstract: The adult mammalian heart has limited regenerative capacity, while the neonatal heart fully regenerates during the first week of life. Postnatal regeneration is mainly driven by proliferation of preexisting cardiomyocytes and supported by proregenerative ...

Abstract	The adult mammalian heart has limited regenerative capacity, while the neonatal heart fully regenerates during the first week of life. Postnatal regeneration is mainly driven by proliferation of preexisting cardiomyocytes and supported by proregenerative macrophages and angiogenesis. Although the process of regeneration has been well studied in the neonatal mouse, the molecular mechanisms that define the switch between regenerative and nonregenerative cardiomyocytes are not well understood. Here, using in vivo and in vitro approaches, we identified the lncRNA Malat1 as a key player in postnatal cardiac regeneration. Malat1 deletion prevented heart regeneration in mice after myocardial infarction on postnatal day 3 associated with a decline in cardiomyocyte proliferation and reparative angiogenesis. Interestingly, Malat1 deficiency increased cardiomyocyte binucleation even in the absence of cardiac injury. Cardiomyocyte-specific deletion of Malat1 was sufficient to block regeneration, supporting a critical role of Malat1 in regulating cardiomyocyte proliferation and binucleation, a landmark of mature nonregenerative cardiomyocytes. In vitro, Malat1 deficiency induced binucleation and the expression of a maturation gene program. Finally, the loss of hnRNP U, an interaction partner of Malat1, induced similar features in vitro, suggesting that Malat1 regulates cardiomyocyte proliferation and binucleation by hnRNP U to control the regenerative window in the heart.
MeSH term(s)	Animals ; Mice ; Heart/physiology ; Heart/physiopathology ; Heart Injuries/genetics ; Heart Injuries/metabolism ; Heart Injuries/physiopathology ; Heterogeneous-Nuclear Ribonucleoprotein U/genetics ; Heterogeneous-Nuclear Ribonucleoprotein U/metabolism ; Macrophages/metabolism ; Macrophages/physiology ; Mammals ; Myocardial Infarction/genetics ; Myocardial Infarction/metabolism ; Myocardial Infarction/physiopathology ; Myocytes, Cardiac/metabolism ; Myocytes, Cardiac/physiology ; Neovascularization, Physiologic/genetics ; Neovascularization, Physiologic/physiology ; Regeneration/genetics ; Regeneration/physiology ; RNA, Long Noncoding/genetics ; RNA, Long Noncoding/metabolism
Chemical Substances	Heterogeneous-Nuclear Ribonucleoprotein U ; MALAT1 long non-coding RNA, human ; RNA, Long Noncoding
Language	English
Publishing date	2023-03-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.162124
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: DNMT3A clonal hematopoiesis-driver mutations induce cardiac fibrosis by paracrine activation of fibroblasts.

Nature communications

2024 Volume 15, Issue 1, Page(s) 606

Abstract: Hematopoietic mutations in epigenetic regulators like DNA methyltransferase 3 alpha (DNMT3A), play a pivotal role in driving clonal hematopoiesis of indeterminate potential (CHIP), and are associated with unfavorable outcomes in patients suffering from ... ...

Abstract	Hematopoietic mutations in epigenetic regulators like DNA methyltransferase 3 alpha (DNMT3A), play a pivotal role in driving clonal hematopoiesis of indeterminate potential (CHIP), and are associated with unfavorable outcomes in patients suffering from heart failure (HF). However, the precise interactions between CHIP-mutated cells and other cardiac cell types remain unknown. Here, we identify fibroblasts as potential partners in interactions with CHIP-mutated monocytes. We used combined transcriptomic data derived from peripheral blood mononuclear cells of HF patients, both with and without CHIP, and cardiac tissue. We demonstrate that inactivation of DNMT3A in macrophages intensifies interactions with cardiac fibroblasts and increases cardiac fibrosis. DNMT3A inactivation amplifies the release of heparin-binding epidermal growth factor-like growth factor, thereby facilitating activation of cardiac fibroblasts. These findings identify a potential pathway of DNMT3A CHIP-driver mutations to the initiation and progression of HF and may also provide a compelling basis for the development of innovative anti-fibrotic strategies.
MeSH term(s)	Humans ; Clonal Hematopoiesis ; DNA (Cytosine-5-)-Methyltransferases/genetics ; DNA Methyltransferase 3A/genetics ; Fibroblasts ; Fibrosis/genetics ; Fibrosis/pathology ; Heart Failure/genetics ; Hematopoiesis/genetics ; Leukocytes, Mononuclear ; Mutation ; Heart Diseases/genetics ; Heart Diseases/pathology
Chemical Substances	DNA (Cytosine-5-)-Methyltransferases (EC 2.1.1.37) ; DNA Methyltransferase 3A (EC 2.1.1.37)
Language	English
Publishing date	2024-01-19
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-43003-w
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Article ; Online: Single-nuclear transcriptome profiling identifies persistent fibroblast activation in hypertrophic and failing human hearts of patients with longstanding disease.

Kattih, Badder / Boeckling, Felicitas / Shumliakivska, Mariana / Tombor, Lukas / Rasper, Tina / Schmitz, Katja / Hoffmann, Jedrzej / Nicin, Luka / Abplanalp, Wesley T / Carstens, Daniel C / Arsalan, Mani / Emrich, Fabian / Holubec, Tomas / Walther, Thomas / Puntmann, Valentina O / Nagel, Eike / John, David / Zeiher, Andreas M / Dimmeler, Stefanie

Cardiovascular research

2023 Volume 119, Issue 15, Page(s) 2550–2562

Abstract: Aims: Cardiac fibrosis drives the progression of heart failure in ischaemic and hypertrophic cardiomyopathy. Therefore, the development of specific anti-fibrotic treatment regimens to counteract cardiac fibrosis is of high clinical relevance. Hence, ... ...

Abstract	Aims: Cardiac fibrosis drives the progression of heart failure in ischaemic and hypertrophic cardiomyopathy. Therefore, the development of specific anti-fibrotic treatment regimens to counteract cardiac fibrosis is of high clinical relevance. Hence, this study examined the presence of persistent fibroblast activation during longstanding human heart disease at a single-cell resolution to identify putative therapeutic targets to counteract pathological cardiac fibrosis in patients. Methods and results: We used single-nuclei RNA sequencing with human tissues from two samples of one healthy donor, and five hypertrophic and two failing hearts. Unsupervised sub-clustering of 7110 nuclei led to the identification of 7 distinct fibroblast clusters. De-convolution of cardiac fibroblast heterogeneity revealed a distinct population of human cardiac fibroblasts with a molecular signature of persistent fibroblast activation and a transcriptional switch towards a pro-fibrotic extra-cellular matrix composition in patients with established cardiac hypertrophy and heart failure. This sub-cluster was characterized by high expression of POSTN, RUNX1, CILP, and a target gene adipocyte enhancer-binding protein 1 (AEBP1) (all P < 0.001). Strikingly, elevated circulating AEBP1 blood level were also detected in a validation cohort of patients with confirmed cardiac fibrosis and hypertrophic cardiomyopathy by cardiac magnetic resonance imaging (P < 0.01). Since endogenous AEBP1 expression was increased in patients with established cardiac hypertrophy and heart failure, we assessed the functional consequence of siRNA-mediated AEBP1 silencing in human cardiac fibroblasts. Indeed, AEBP1 silencing reduced proliferation, migration, and fibroblast contractile capacity and α-SMA gene expression, which is a hallmark of fibroblast activation (all P < 0.05). Mechanistically, the anti-fibrotic effects of AEBP1 silencing were linked to transforming growth factor-beta pathway modulation. Conclusion: Together, this study identifies persistent fibroblast activation in patients with longstanding heart disease, which might be detected by circulating AEBP1 and therapeutically modulated by its targeted silencing in human cardiac fibroblasts.
MeSH term(s)	Humans ; Heart Failure/metabolism ; Heart Diseases/pathology ; Cardiomegaly/metabolism ; Cardiomyopathy, Hypertrophic/metabolism ; Cardiomyopathies/metabolism ; Fibrosis ; Fibroblasts/metabolism ; Gene Expression Profiling ; Carboxypeptidases/metabolism ; Repressor Proteins/metabolism
Chemical Substances	AEBP1 protein, human ; Carboxypeptidases (EC 3.4.-) ; Repressor Proteins
Language	English
Publishing date	2023-08-30
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80340-6
ISSN	1755-3245 ; 0008-6363
ISSN (online)	1755-3245
ISSN	0008-6363
DOI	10.1093/cvr/cvad140
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Article ; Online: Identification of novel antiviral drug candidates using an optimized SARS-CoV-2 phenotypic screening platform.

Bojkova, Denisa / Reus, Philipp / Panosch, Leona / Bechtel, Marco / Rothenburger, Tamara / Kandler, Joshua D / Pfeiffer, Annika / Wagner, Julian U G / Shumliakivska, Mariana / Dimmeler, Stefanie / Olmer, Ruth / Martin, Ulrich / Vondran, Florian W R / Toptan, Tuna / Rothweiler, Florian / Zehner, Richard / Rabenau, Holger F / Osman, Karen L / Pullan, Steven T /

Carroll, Miles W / Stack, Richard / Ciesek, Sandra / Wass, Mark N / Michaelis, Martin / Cinatl, Jindrich

iScience

2023 Volume 26, Issue 2, Page(s) 105944

Abstract: Reliable, easy-to-handle phenotypic screening platforms are needed for the identification of anti-SARS-CoV-2 compounds. Here, we present caspase 3/7 activity as a readout for monitoring the replication of SARS-CoV-2 isolates from different variants, ... ...

Abstract	Reliable, easy-to-handle phenotypic screening platforms are needed for the identification of anti-SARS-CoV-2 compounds. Here, we present caspase 3/7 activity as a readout for monitoring the replication of SARS-CoV-2 isolates from different variants, including a remdesivir-resistant strain, and of other coronaviruses in numerous cell culture models, independently of cytopathogenic effect formation. Compared to other models, the Caco-2 subline Caco-2-F03 displayed superior performance. It possesses a stable SARS-CoV-2 susceptibility phenotype and does not produce false-positive hits due to drug-induced phospholipidosis. A proof-of-concept screen of 1,796 kinase inhibitors identified known and novel antiviral drug candidates including inhibitors of phosphoglycerate dehydrogenase (PHGDH), CDC like kinase 1 (CLK-1), and colony stimulating factor 1 receptor (CSF1R). The activity of the PHGDH inhibitor NCT-503 was further increased in combination with the hexokinase II (HK2) inhibitor 2-deoxy-D-glucose, which is in clinical development for COVID-19. In conclusion, caspase 3/7 activity detection in SARS-CoV-2-infected Caco-2-F03 cells provides a simple phenotypic high-throughput screening platform for SARS-CoV-2 drug candidates that reduces false-positive hits.
Language	English
Publishing date	2023-01-07
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2023.105944
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Article ; Online: Increased susceptibility of human endothelial cells to infections by SARS-CoV-2 variants.

Wagner, Julian U G / Bojkova, Denisa / Shumliakivska, Mariana / Luxán, Guillermo / Nicin, Luka / Aslan, Galip S / Milting, Hendrik / Kandler, Joshua D / Dendorfer, Andreas / Heumueller, Andreas W / Fleming, Ingrid / Bibli, Sofia-Iris / Jakobi, Tobias / Dieterich, Christoph / Zeiher, Andreas M / Ciesek, Sandra / Cinatl, Jindrich / Dimmeler, Stefanie

Basic research in cardiology

2021 Volume 116, Issue 1, Page(s) 42

Abstract: Coronavirus disease 2019 (COVID-19) spawned a global health crisis in late 2019 and is caused by the novel coronavirus SARS-CoV-2. SARS-CoV-2 infection can lead to elevated markers of endothelial dysfunction associated with higher risk of mortality. It ... ...

Abstract	Coronavirus disease 2019 (COVID-19) spawned a global health crisis in late 2019 and is caused by the novel coronavirus SARS-CoV-2. SARS-CoV-2 infection can lead to elevated markers of endothelial dysfunction associated with higher risk of mortality. It is unclear whether endothelial dysfunction is caused by direct infection of endothelial cells or is mainly secondary to inflammation. Here, we investigate whether different types of endothelial cells are susceptible to SARS-CoV-2. Human endothelial cells from different vascular beds including umbilical vein endothelial cells, coronary artery endothelial cells (HCAEC), cardiac and lung microvascular endothelial cells, or pulmonary arterial cells were inoculated in vitro with SARS-CoV-2. Viral spike protein was only detected in HCAECs after SARS-CoV-2 infection but not in the other endothelial cells tested. Consistently, only HCAEC expressed the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2), required for virus infection. Infection with the SARS-CoV-2 variants B.1.1.7, B.1.351, and P.2 resulted in significantly higher levels of viral spike protein. Despite this, no intracellular double-stranded viral RNA was detected and the supernatant did not contain infectious virus. Analysis of the cellular distribution of the spike protein revealed that it co-localized with endosomal calnexin. SARS-CoV-2 infection did induce the ER stress gene EDEM1, which is responsible for clearance of misfolded proteins from the ER. Whereas the wild type of SARS-CoV-2 did not induce cytotoxic or pro-inflammatory effects, the variant B.1.1.7 reduced the HCAEC cell number. Of the different tested endothelial cells, HCAECs showed highest viral uptake but did not promote virus replication. Effects on cell number were only observed after infection with the variant B.1.1.7, suggesting that endothelial protection may be particularly important in patients infected with this variant.
MeSH term(s)	Angiotensin-Converting Enzyme 2/metabolism ; Calnexin/metabolism ; Cells, Cultured ; Endoplasmic Reticulum/metabolism ; Endoplasmic Reticulum/virology ; Endoplasmic Reticulum Stress ; Endothelial Cells/metabolism ; Endothelial Cells/virology ; Host-Pathogen Interactions ; Humans ; Membrane Proteins/metabolism ; Receptors, Virus/metabolism ; SARS-CoV-2/genetics ; SARS-CoV-2/metabolism ; SARS-CoV-2/pathogenicity ; Spike Glycoprotein, Coronavirus/metabolism
Chemical Substances	CANX protein, human ; EDEM1 protein, human ; Membrane Proteins ; Receptors, Virus ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; Calnexin (139873-08-8) ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
Language	English
Publishing date	2021-07-05
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	189755-x
ISSN	1435-1803 ; 0300-8428 ; 0175-9418
ISSN (online)	1435-1803
ISSN	0300-8428 ; 0175-9418
DOI	10.1007/s00395-021-00882-8
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Article ; Online: Identification of novel antiviral drug candidates using an optimized SARS-CoV-2 phenotypic screening platform

Bojkova, Denisa / Reus, Philipp / Panosch, Leona / Bechtel, Marco / Rothenburger, Tamara / Kandler, Joshua / Pfeiffer, Annika / Wagner, Julian UG / Shumliakivska, Mariana / Dimmeler, Stefanie / Olmer, Ruth / Martin, Ulrich / Vondran, Florian / Toptan, Tuna / Rothweiler, Florian / Zehner, Richard / Rabenau, Holger / Osman, Karen L / Pullan, Steven T /

Carroll, Miles T / Stack, Richard / Ciesek, Sandra / Wass, Mark N / Michaelis, Martin / Cinatl, Jindrich

bioRxiv

Abstract: Reliable, easy-to-handle phenotypic screening platforms are needed for the identification of anti-SARS-CoV-2 compounds. Here, we present caspase 3/7 activity as a read-out for monitoring the replication of SARS-CoV-2 isolates from different variants, ... ...

Abstract	Reliable, easy-to-handle phenotypic screening platforms are needed for the identification of anti-SARS-CoV-2 compounds. Here, we present caspase 3/7 activity as a read-out for monitoring the replication of SARS-CoV-2 isolates from different variants, including a remdesivir-resistant strain, and of other coronaviruses in a broad range of cell culture models, independently of cytopathogenic effect formation. Compared to other cell culture models, the Caco-2 subline Caco-2-F03 displayed superior performance, as it possesses a stable SARS-CoV-2 susceptible phenotype and does not produce false-positive hits due to drug-induced phospholipidosis. A proof-of-concept screen of 1796 kinase inhibitors identified known and novel antiviral drug candidates including inhibitors of PHGDH, CLK-1, and CSF1R. The activity of the PHGDH inhibitor NCT-503 was further increased in combination with the HK2 inhibitor 2-deoxy-D-glucose, which is in clinical development for COVID-19. In conclusion, caspase 3/7 activity detection in SARS-CoV-2-infected Caco-2F03 cells provides a simple phenotypic high-throughput screening platform for SARS-CoV-2 drug candidates that reduces false positive hits.
Keywords	covid19
Language	English
Publishing date	2022-07-17
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2022.07.17.500346
Database	COVID19

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Article ; Online: SARS-CoV-2 infects and induces cytotoxic effects in human cardiomyocytes.

Cardiovascular research

2020 Volume 116, Issue 14, Page(s) 2207–2215

Abstract: Aims: Coronavirus disease 2019 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has emerged as a global pandemic. SARS-CoV-2 infection can lead to elevated markers of cardiac injury associated with higher risk of mortality. ... ...

Abstract	Aims: Coronavirus disease 2019 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has emerged as a global pandemic. SARS-CoV-2 infection can lead to elevated markers of cardiac injury associated with higher risk of mortality. It is unclear whether cardiac injury is caused by direct infection of cardiomyocytes or is mainly secondary to lung injury and inflammation. Here, we investigate whether cardiomyocytes are permissive for SARS-CoV-2 infection. Methods and results: Two strains of SARS-CoV-2 infected human induced pluripotent stem cell-derived cardiomyocytes as demonstrated by detection of intracellular double-stranded viral RNA and viral spike glycoprotein expression. Increasing concentrations of viral RNA are detected in supernatants of infected cardiomyocytes, which induced infections in Caco-2 cell lines, documenting productive infections. SARS-CoV-2 infection and induced cytotoxic and proapoptotic effects associated with it abolished cardiomyocyte beating. RNA sequencing confirmed a transcriptional response to viral infection as demonstrated by the up-regulation of genes associated with pathways related to viral response and interferon signalling, apoptosis, and reactive oxygen stress. SARS-CoV-2 infection and cardiotoxicity was confirmed in a 3D cardiosphere tissue model. Importantly, viral spike protein and viral particles were detected in living human heart slices after infection with SARS-CoV-2. Coronavirus particles were further observed in cardiomyocytes of a patient with coronavirus disease 2019. Infection of induced pluripotent stem cell-derived cardiomyocytes was dependent on cathepsins and angiotensin-converting enzyme 2, and was blocked by remdesivir. Conclusion: This study demonstrates that SARS-CoV-2 infects cardiomyocytes in vitro in an angiotensin-converting enzyme 2- and cathepsin-dependent manner. SARS-CoV-2 infection of cardiomyocytes is inhibited by the antiviral drug remdesivir.
MeSH term(s)	Adenosine Monophosphate/analogs & derivatives ; Adenosine Monophosphate/pharmacology ; Alanine/analogs & derivatives ; Alanine/pharmacology ; Angiotensin-Converting Enzyme 2/metabolism ; Antiviral Agents/pharmacology ; Apoptosis/drug effects ; COVID-19/drug therapy ; COVID-19/metabolism ; COVID-19/pathology ; COVID-19/virology ; Caco-2 Cells ; Cathepsins/metabolism ; Heart Diseases/drug therapy ; Heart Diseases/metabolism ; Heart Diseases/pathology ; Heart Diseases/virology ; Host-Pathogen Interactions ; Humans ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/metabolism ; Myocytes, Cardiac/pathology ; Myocytes, Cardiac/virology ; Reactive Oxygen Species/metabolism ; SARS-CoV-2/drug effects ; SARS-CoV-2/pathogenicity ; Signal Transduction
Chemical Substances	Antiviral Agents ; Reactive Oxygen Species ; remdesivir (3QKI37EEHE) ; Adenosine Monophosphate (415SHH325A) ; Cathepsins (EC 3.4.-) ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Alanine (OF5P57N2ZX)
Keywords	covid19
Language	English
Publishing date	2020-11-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80340-6
ISSN	1755-3245 ; 0008-6363
ISSN (online)	1755-3245
ISSN	0008-6363
DOI	10.1093/cvr/cvaa267
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Article ; Online: Angiotensin II receptor blocker intake associates with reduced markers of inflammatory activation and decreased mortality in patients with cardiovascular comorbidities and COVID-19 disease.

Cremer, Sebastian / Pilgram, Lisa / Berkowitsch, Alexander / Stecher, Melanie / Rieg, Siegbert / Shumliakivska, Mariana / Bojkova, Denisa / Wagner, Julian Uwe Gabriel / Aslan, Galip Servet / Spinner, Christoph / Luxán, Guillermo / Hanses, Frank / Dolff, Sebastian / Piepel, Christiane / Ruppert, Clemens / Guenther, Andreas / Rüthrich, Maria Madeleine / Vehreschild, Jörg Janne / Wille, Kai /

Haselberger, Martina / Heuzeroth, Hanno / Hansen, Arne / Eschenhagen, Thomas / Cinatl, Jindrich / Ciesek, Sandra / Dimmeler, Stefanie / Borgmann, Stefan / Zeiher, Andreas

PloS one

2021 Volume 16, Issue 10, Page(s) e0258684

Abstract: Aims: Patients with cardiovascular comorbidities have a significantly increased risk for a critical course of COVID-19. As the SARS-CoV2 virus enters cells via the angiotensin-converting enzyme receptor II (ACE2), drugs which interact with the renin ... ...

Abstract	Aims: Patients with cardiovascular comorbidities have a significantly increased risk for a critical course of COVID-19. As the SARS-CoV2 virus enters cells via the angiotensin-converting enzyme receptor II (ACE2), drugs which interact with the renin angiotensin aldosterone system (RAAS) were suspected to influence disease severity. Methods and results: We analyzed 1946 consecutive patients with cardiovascular comorbidities or hypertension enrolled in one of the largest European COVID-19 registries, the Lean European Open Survey on SARS-CoV-2 (LEOSS) registry. Here, we show that angiotensin II receptor blocker intake is associated with decreased mortality in patients with COVID-19 [OR 0.75 (95% CI 0,59-0.96; p = 0.013)]. This effect was mainly driven by patients, who presented in an early phase of COVID-19 at baseline [OR 0,64 (95% CI 0,43-0,96; p = 0.029)]. Kaplan-Meier analysis revealed a significantly lower incidence of death in patients on an angiotensin receptor blocker (ARB) (n = 33/318;10,4%) compared to patients using an angiotensin-converting enzyme inhibitor (ACEi) (n = 60/348;17,2%) or patients who received neither an ACE-inhibitor nor an ARB at baseline in the uncomplicated phase (n = 90/466; 19,3%; p<0.034). Patients taking an ARB were significantly less frequently reaching the mortality predicting threshold for leukocytes (p<0.001), neutrophils (p = 0.002) and the inflammatory markers CRP (p = 0.021), procalcitonin (p = 0.001) and IL-6 (p = 0.049). ACE2 expression levels in human lung samples were not altered in patients taking RAAS modulators. Conclusion: These data suggest a beneficial effect of ARBs on disease severity in patients with cardiovascular comorbidities and COVID-19, which is linked to dampened systemic inflammatory activity.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Angiotensin Receptor Antagonists/administration & dosage ; Angiotensin-Converting Enzyme Inhibitors/administration & dosage ; Biomarkers/blood ; COVID-19/blood ; COVID-19/drug therapy ; COVID-19/mortality ; Comorbidity ; Disease-Free Survival ; Female ; Humans ; Hypertension/blood ; Hypertension/drug therapy ; Hypertension/mortality ; Inflammation/blood ; Inflammation/drug therapy ; Inflammation/mortality ; Male ; Middle Aged ; Registries ; SARS-CoV-2/metabolism ; Severity of Illness Index ; Survival Rate
Chemical Substances	Angiotensin Receptor Antagonists ; Angiotensin-Converting Enzyme Inhibitors ; Biomarkers
Language	English
Publishing date	2021-10-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0258684
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Article ; Online: SARS-CoV-2 infects and induces cytotoxic effects in human cardiomyocytes

bioRxiv

Abstract: Background The coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has emerged as global pandemic. SARS-CoV-2 infection can lead to elevated markers of cardiac injury associated with higher ... ...

Abstract	Background The coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has emerged as global pandemic. SARS-CoV-2 infection can lead to elevated markers of cardiac injury associated with higher risk of mortality in COVID-19 patients. It is unclear whether cardiac injury may have been caused by direct infection of cardiomyocytes or is mainly secondary to lung injury and inflammation. Here we investigate whether human cardiomyocytes are permissive for SARS-CoV-2 infection. Methods Infection was induced by two strains of SARS-CoV-2 (FFM1 and FFM2) in human induced pluripotent stem cells-derived cardiomyocytes (hiPS-CM) and in two models of human cardiac tissue. Results We show that SARS-CoV-2 infects hiPS-CM as demonstrated by detection of intracellular double strand viral RNA and viral spike glycoprotein protein expression. Increasing concentrations of virus RNA are detected in supernatants of infected cardiomyocytes, which induced infections in CaCo-2 cell lines documenting productive infections. SARS-COV-2 infection induced cytotoxic and pro-apoptotic effects and abolished cardiomyocyte beating. RNA sequencing confirmed a transcriptional response to viral infection as demonstrated by the up-regulation of genes associated with pathways related to viral response and interferon signaling, apoptosis and reactive oxygen stress. SARS-CoV-2 infection and cardiotoxicity was confirmed in a iPS-derived human 3D cardiosphere tissue models. Importantly, viral spike protein and viral particles were detected in living human heart slices after infection with SARS-CoV-2. Conclusions The demonstration that cardiomyocytes are permissive for SARS-CoV-2 infection in vitro warrants the further in depth monitoring of cardiotoxic effects in COVID-19 patients. Clinical Perspective What is New? This study demonstrates that human cardiac myocytes are permissive for SARS-CoV-2 infection. The study documents that SARS-CoV-2 undergoes a full replicatory circle and induces a cytotoxic response in cardiomyocytes. Infection was confirmed in two cardiac tissue models, including living human heart slices. What are the Clinical Implications? The study may provide a rational to explain part of the cardiotoxicity observed in COVID-19 patients The demonstration of direct cardiotoxicity induced by SARS-CoV-2 warrants an in depth further analysis of cardiac tissue of COVID-19 patients and a close monitoring for putative direct cardiomyocyte injury. The established models can be used to test novel therapeutic approaches targeting COVID-19.
Keywords	covid19
Publisher	BioRxiv; WHO
Document type	Article ; Online
DOI	10.1101/2020.06.01.127605
Database	COVID19

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Article: SARS-CoV-2 infects and induces cytotoxic effects in human cardiomyocytes

Cardiovasc. res

Abstract: AIMS: Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has emerged as a global pandemic. SARS-CoV-2 infection can lead to elevated markers of cardiac injury associated with higher risk of ... ...

Abstract	AIMS: Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has emerged as a global pandemic. SARS-CoV-2 infection can lead to elevated markers of cardiac injury associated with higher risk of mortality. It is unclear whether cardiac injury is caused by direct infection of cardiomyocytes or is mainly secondary to lung injury and inflammation. Here, we investigate whether cardiomyocytes are permissive for SARS-CoV-2 infection. METHODS AND RESULTS: Two strains of SARS-CoV-2 infected human induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) as demonstrated by detection of intracellular double-stranded viral RNA and viral spike glycoprotein expression. Increasing concentrations of viral RNA are detected in supernatants of infected cardiomyocytes, which induced infections in Caco-2 cell lines, documenting productive infections. SARS-COV-2 infection and induced cytotoxic and proapoptotic effects associated with it abolished cardiomyocyte beating. RNA sequencing confirmed a transcriptional response to viral infection as demonstrated by the up-regulation of genes associated with pathways related to viral response and interferon signalling, apoptosis, and reactive oxygen stress. SARS-CoV-2 infection and cardiotoxicity was confirmed in a 3D cardiosphere tissue model. Importantly, viral spike protein and viral particles were detected in living human heart slices after infection with SARS-CoV-2. Coronavirus particles were further observed in cardiomyocytes of a patient with COVID-19. Infection of iPS-CMs was dependent on cathepsins and angiotensin-converting enzyme 2 (ACE2), and was blocked by remdesivir. CONCLUSIONS: This study demonstrates that SARS-CoV-2 infects cardiomyocytes in vitro in an ACE2- and cathepsin-dependent manner. SARS-CoV-2 infection of cardiomyocytes is inhibited by the antiviral drug remdesivir. TRANSLATIONAL PERSPECTIVE: Although this study cannot address whether cardiac injury and dysfunction in COVID-19 patients is caused by direct infection of cardiomyocytes, the demonstration of direct cardiotoxicity in cardiomyocytes, organ mimics, human heart slices and human hearts warrants the further monitoring of cardiotoxic effects in COVID-19 patients.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #787151
Database	COVID19

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