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Article: Fibroblast‐mediated intercellular crosstalk in the healthy and diseased heart

Nicin, Luka / Wagner, Julian U. G. / Luxán, Guillermo / Dimmeler, Stefanie

FEBS letters. 2022 Mar., v. 596, no. 5

2022

Abstract: Cardiac fibroblasts constitute a major cell population in the heart. They secrete extracellular matrix components and various other factors shaping the microenvironment of the heart. In silico analysis of intercellular communication based on single‐cell ... ...

Abstract	Cardiac fibroblasts constitute a major cell population in the heart. They secrete extracellular matrix components and various other factors shaping the microenvironment of the heart. In silico analysis of intercellular communication based on single‐cell RNA sequencing revealed that fibroblasts are the source of the majority of outgoing signals to other cell types. This observation suggests that fibroblasts play key roles in orchestrating cellular interactions that maintain organ homeostasis but that can also contribute to disease states. Here, we will review the current knowledge of fibroblast interactions in the healthy, diseased, and aging heart. We focus on the interactions that fibroblasts establish with other cells of the heart, specifically cardiomyocytes, endothelial cells and immune cells, and particularly those relying on paracrine, electrical, and exosomal communication modes.
Keywords	RNA ; cardiomyocytes ; cell communication ; computer simulation ; extracellular matrix ; fibroblasts ; homeostasis
Language	English
Dates of publication	2022-03
Size	p. 638-654.
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	REVIEW
ZDB-ID	212746-5
ISSN	1873-3468 ; 0014-5793
ISSN (online)	1873-3468
ISSN	0014-5793
DOI	10.1002/1873-3468.14234
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Article ; Online: Fibroblast-mediated intercellular crosstalk in the healthy and diseased heart.

Nicin, Luka / Wagner, Julian U G / Luxán, Guillermo / Dimmeler, Stefanie

FEBS letters

2021 Volume 596, Issue 5, Page(s) 638–654

Abstract	Cardiac fibroblasts constitute a major cell population in the heart. They secrete extracellular matrix components and various other factors shaping the microenvironment of the heart. In silico analysis of intercellular communication based on single-cell RNA sequencing revealed that fibroblasts are the source of the majority of outgoing signals to other cell types. This observation suggests that fibroblasts play key roles in orchestrating cellular interactions that maintain organ homeostasis but that can also contribute to disease states. Here, we will review the current knowledge of fibroblast interactions in the healthy, diseased, and aging heart. We focus on the interactions that fibroblasts establish with other cells of the heart, specifically cardiomyocytes, endothelial cells and immune cells, and particularly those relying on paracrine, electrical, and exosomal communication modes.
MeSH term(s)	Cell Communication ; Endothelial Cells ; Fibroblasts/metabolism ; Myocytes, Cardiac/metabolism
Language	English
Publishing date	2021-12-01
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	212746-5
ISSN	1873-3468 ; 0014-5793
ISSN (online)	1873-3468
ISSN	0014-5793
DOI	10.1002/1873-3468.14234
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Article ; Online: Cardiomyocyte hyperplasia and immaturity but not hypertrophy are characteristic features of patients with RASopathies.

Drenckhahn, Jörg-Detlef / Nicin, Luka / Akhouaji, Sara / Krück, Svenja / Blank, Anna Eva / Schänzer, Anne / Yörüker, Uygar / Jux, Christian / Tombor, Lukas / Abplanalp, Wesley / John, David / Zeiher, Andreas M / Dimmeler, Stefanie / Rupp, Stefan

Journal of molecular and cellular cardiology

2023 Volume 178, Page(s) 22–35

Abstract: Aims: RASopathies are caused by mutations in genes that alter the MAP kinase pathway and are marked by several malformations with cardiovascular disorders as the predominant cause of mortality. Mechanistic insights in the underlying pathogenesis in ... ...

Abstract	Aims: RASopathies are caused by mutations in genes that alter the MAP kinase pathway and are marked by several malformations with cardiovascular disorders as the predominant cause of mortality. Mechanistic insights in the underlying pathogenesis in affected cardiac tissue are rare. The aim of the study was to assess the impact of RASopathy causing mutations on the human heart. Methods and results: Using single cell approaches and histopathology we analyzed cardiac tissue from children with different RASopathy-associated mutations compared to age-matched dilated cardiomyopathy (DCM) and control hearts. The volume of cardiomyocytes was reduced in RASopathy conditions compared to controls and DCM patients, and the estimated number of cardiomyocytes per heart was ∼4-10 times higher. Single nuclei RNA sequencing of a 13-year-old RASopathy patient (carrying a PTPN11 c.1528C > G mutation) revealed that myocardial cell composition and transcriptional patterns were similar to <1 year old DCM hearts. Additionally, immaturity of cardiomyocytes is shown by an increased MYH6/MYH7 expression ratio and reduced expression of genes associated with fatty acid metabolism. In the patient with the PTPN11 mutation activation of the MAP kinase pathway was not evident in cardiomyocytes, whereas increased phosphorylation of PDK1 and its downstream kinase Akt was detected. Conclusion: In conclusion, an immature cardiomyocyte differentiation status appears to be preserved in juvenile RASopathy patients. The increased mass of the heart in such patients is due to an increase in cardiomyocyte number (hyperplasia) but not an enlargement of individual cardiomyocytes (hypertrophy).
MeSH term(s)	Child ; Infant ; Humans ; Adolescent ; Myocytes, Cardiac/metabolism ; Hyperplasia/metabolism ; Mutation ; Mitogen-Activated Protein Kinases/metabolism ; Hypertrophy/metabolism ; Cardiomyopathy, Dilated/genetics ; Cardiomyopathy, Dilated/metabolism
Chemical Substances	Mitogen-Activated Protein Kinases (EC 2.7.11.24)
Language	English
Publishing date	2023-03-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80157-4
ISSN	1095-8584 ; 0022-2828
ISSN (online)	1095-8584
ISSN	0022-2828
DOI	10.1016/j.yjmcc.2023.03.003
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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: Endothelial cells drive organ fibrosis in mice by inducing expression of the transcription factor SOX9.

Trogisch, Felix A / Abouissa, Aya / Keles, Merve / Birke, Anne / Fuhrmann, Manuela / Dittrich, Gesine M / Weinzierl, Nina / Wink, Elvira / Cordero, Julio / Elsherbiny, Adel / Martin-Garrido, Abel / Grein, Steve / Hemanna, Shruthi / Hofmann, Ellen / Nicin, Luka / Bibli, Sofia-Iris / Airik, Rannar / Kispert, Andreas / Kist, Ralf /

Quanchao, Sun / Kürschner, Sina W / Winkler, Manuel / Gretz, Norbert / Mogler, Carolin / Korff, Thomas / Koch, Philipp-Sebastian / Dimmeler, Stefanie / Dobreva, Gergana / Heineke, Joerg

Science translational medicine

2024 Volume 16, Issue 736, Page(s) eabq4581

Abstract: Fibrosis is a hallmark of chronic disease. Although fibroblasts are involved, it is unclear to what extent endothelial cells also might contribute. We detected increased expression of the transcription ... ...

Abstract	Fibrosis is a hallmark of chronic disease. Although fibroblasts are involved, it is unclear to what extent endothelial cells also might contribute. We detected increased expression of the transcription factor
MeSH term(s)	Animals ; Humans ; Mice ; Disease Models, Animal ; Endothelial Cells ; Fibrosis ; Heart Failure ; Intercellular Signaling Peptides and Proteins ; Liver Cirrhosis/complications ; SOX9 Transcription Factor/genetics ; Transcription Factors
Chemical Substances	Intercellular Signaling Peptides and Proteins ; SOX9 protein, human ; SOX9 Transcription Factor ; Transcription Factors ; Sox9 protein, mouse
Language	English
Publishing date	2024-02-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.abq4581
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Article ; Online: Cell type-specific expression of the putative SARS-CoV-2 receptor ACE2 in human hearts.

Nicin, Luka / Abplanalp, Wesley Tyler / Mellentin, Hannah / Kattih, Badder / Tombor, Lukas / John, David / Schmitto, Jan D / Heineke, Jörg / Emrich, Fabian / Arsalan, Mani / Holubec, Tomas / Walther, Thomas / Zeiher, Andreas M / Dimmeler, Stefanie

European heart journal

2020 Volume 41, Issue 19, Page(s) 1804–1806

MeSH term(s)	Aged ; Aged, 80 and over ; Angiotensin-Converting Enzyme 2 ; Betacoronavirus ; COVID-19 ; Case-Control Studies ; Cell Nucleus/genetics ; Coronavirus Infections ; Female ; Gene Expression ; Humans ; Male ; Middle Aged ; Myocardium/cytology ; Myocytes, Cardiac/metabolism ; Pandemics ; Peptidyl-Dipeptidase A/genetics ; Peptidyl-Dipeptidase A/metabolism ; Pneumonia, Viral ; SARS-CoV-2 ; Sequence Analysis, RNA
Chemical Substances	ACE protein, human (EC 3.4.15.1) ; Peptidyl-Dipeptidase A (EC 3.4.15.1) ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
Keywords	covid19
Language	English
Publishing date	2020-04-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	603098-1
ISSN	1522-9645 ; 0195-668X
ISSN (online)	1522-9645
ISSN	0195-668X
DOI	10.1093/eurheartj/ehaa311
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Article ; Online: An In Vitro Model for Identifying Cardiac Side Effects of Anesthetics.

Chang, Alex C Y / Chang, Andrew C H / Nicin, Luka / Weber, Gerhard J / Holbrook, Colin / Davies, M Frances / Blau, Helen M / Bertaccini, Edward J

Anesthesia and analgesia

2018 Volume 130, Issue 1, Page(s) e1–e4

Abstract: The understanding of anesthetic side effects on the heart has been hindered by the lack of sophisticated clinical models. Using micropatterned human-induced pluripotent stem cell-derived cardiomyocytes, we obtained cardiac muscle depressant profiles for ... ...

Abstract	The understanding of anesthetic side effects on the heart has been hindered by the lack of sophisticated clinical models. Using micropatterned human-induced pluripotent stem cell-derived cardiomyocytes, we obtained cardiac muscle depressant profiles for propofol, etomidate, and our newly identified anesthetic compound KSEB01-S2. Propofol was the strongest depressant among the 3 compounds tested, exhibiting the largest decrease in contraction velocity, depression rate, and beating frequency. Interestingly, KSEB01-S2 behaved similarly to etomidate, suggesting a better cardiac safety profile. Our results provide a proof-of-concept for using human-induced pluripotent stem cell-derived cardiomyocytes as an in vitro platform for future drug design.
MeSH term(s)	Adult ; Anesthetics, Intravenous/toxicity ; Cardiotoxicity ; Cell Line ; Etomidate/toxicity ; Female ; Heart Diseases/chemically induced ; Heart Diseases/pathology ; Heart Diseases/physiopathology ; Heart Rate/drug effects ; Humans ; Induced Pluripotent Stem Cells/drug effects ; Induced Pluripotent Stem Cells/pathology ; Male ; Middle Aged ; Myocardial Contraction/drug effects ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/pathology ; Proof of Concept Study ; Propofol/toxicity ; Risk Assessment ; Time Factors ; Young Adult
Chemical Substances	Anesthetics, Intravenous ; Propofol (YI7VU623SF) ; Etomidate (Z22628B598)
Language	English
Publishing date	2018-08-31
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Video-Audio Media
ZDB-ID	80032-6
ISSN	1526-7598 ; 0003-2999
ISSN (online)	1526-7598
ISSN	0003-2999
DOI	10.1213/ANE.0000000000003757
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Article ; Online: Single Nuclei Sequencing Reveals Novel Insights Into the Regulation of Cellular Signatures in Children With Dilated Cardiomyopathy.

Nicin, Luka / Abplanalp, Wesley T / Schänzer, Anne / Sprengel, Anke / John, David / Mellentin, Hannah / Tombor, Lukas / Keuper, Matthias / Ullrich, Evelyn / Klingel, Karin / Dettmeyer, Reinhard B / Hoffmann, Jedrzej / Akintuerk, Hakan / Jux, Christian / Schranz, Dietmar / Zeiher, Andreas M / Rupp, Stefan / Dimmeler, Stefanie

Circulation

2021 Volume 143, Issue 17, Page(s) 1704–1719

Abstract: Background: Dilated cardiomyopathy (DCM) is a leading cause of death in children with heart failure. The outcome of pediatric heart failure treatment is inconsistent, and large cohort studies are lacking. Progress may be achieved through personalized ... ...

Abstract	Background: Dilated cardiomyopathy (DCM) is a leading cause of death in children with heart failure. The outcome of pediatric heart failure treatment is inconsistent, and large cohort studies are lacking. Progress may be achieved through personalized therapy that takes age- and disease-related pathophysiology, pathology, and molecular fingerprints into account. We present single nuclei RNA sequencing from pediatric patients with DCM as the next step in identifying cellular signatures. Methods: We performed single nuclei RNA sequencing with heart tissues from 6 children with DCM with an age of 0.5, 0.75, 5, 6, 12, and 13 years. Unsupervised clustering of 18 211 nuclei led to the identification of 14 distinct clusters with 6 major cell types. Results: The number of nuclei in fibroblast clusters increased with age in patients with DCM, a finding that was confirmed by histological analysis and was consistent with an age-related increase in cardiac fibrosis quantified by cardiac magnetic resonance imaging. Fibroblasts of patients with DCM >6 years of age showed a profoundly altered gene expression pattern with enrichment of genes encoding fibrillary collagens, modulation of proteoglycans, switch in thrombospondin isoforms, and signatures of fibroblast activation. In addition, a population of cardiomyocytes with a high proregenerative profile was identified in infant patients with DCM but was absent in children >6 years of age. This cluster showed high expression of cell cycle activators such as Conclusions: Novel insights into the cellular transcriptomes of hearts from pediatric patients with DCM provide remarkable age-dependent changes in the expression patterns of fibroblast and cardiomyocyte genes with less fibrotic but enriched proregenerative signatures in infants.
MeSH term(s)	Cardiomyopathy, Dilated/genetics ; Cardiomyopathy, Dilated/pathology ; Cell Proliferation ; Child ; Child, Preschool ; Female ; High-Throughput Nucleotide Sequencing/methods ; Humans ; Male ; Sequence Analysis, RNA/methods
Language	English
Publishing date	2021-02-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80099-5
ISSN	1524-4539 ; 0009-7322 ; 0069-4193 ; 0065-8499
ISSN (online)	1524-4539
ISSN	0009-7322 ; 0069-4193 ; 0065-8499
DOI	10.1161/CIRCULATIONAHA.120.051391
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Article ; Online: Ethyl pyruvate ameliorates hepatic injury following blunt chest trauma and hemorrhagic shock by reducing local inflammation, NF-kappaB activation and HMGB1 release.

Wagner, Nils / Dieteren, Scott / Franz, Niklas / Köhler, Kernt / Mörs, Katharina / Nicin, Luka / Schmidt, Julia / Perl, Mario / Marzi, Ingo / Relja, Borna

PloS one

2018 Volume 13, Issue 2, Page(s) e0192171

Abstract: Background: The treatment of patients with multiple trauma including blunt chest/thoracic trauma (TxT) and hemorrhagic shock (H) is still challenging. Numerous studies show detrimental consequences of TxT and HS resulting in strong inflammatory changes, ...

Abstract	Background: The treatment of patients with multiple trauma including blunt chest/thoracic trauma (TxT) and hemorrhagic shock (H) is still challenging. Numerous studies show detrimental consequences of TxT and HS resulting in strong inflammatory changes, organ injury and mortality. Additionally, the reperfusion (R) phase plays a key role in triggering inflammation and worsening outcome. Ethyl pyruvate (EP), a stable lipophilic ester, has anti-inflammatory properties. Here, the influence of EP on the inflammatory reaction and liver injury in a double hit model of TxT and H/R in rats was explored. Methods: Female Lewis rats were subjected to TxT followed by hemorrhage/H (60 min, 35±3 mm Hg) and resuscitation/R (TxT+H/R). Reperfusion was performed by either Ringer`s lactated solution (RL) alone or RL supplemented with EP (50 mg/kg). Sham animals underwent all surgical procedures without TxT+H/R. After 2h, blood and liver tissue were collected for analyses, and survival was assessed after 24h. Results: Resuscitation with EP significantly improved haemoglobin levels and base excess recovery compared with controls after TxT+H/R, respectively (p<0.05). TxT+H/R-induced significant increase in alanine aminotransferase levels and liver injury were attenuated by EP compared with controls (p<0.05). Local inflammation as shown by increased gene expression of IL-6 and ICAM-1, enhanced ICAM-1 and HMGB1 protein expression and infiltration of the liver with neutrophils were also significantly attenuated by EP compared with controls after TxT+H/R (p<0.05). EP significantly reduced TxT+H/R-induced p65 activation in liver tissue. Survival rates improved by EP from 50% to 70% after TxT+H/R. Conclusions: These data support the concept that the pronounced local pro-inflammatory response in the liver after blunt chest trauma and hemorrhagic shock is associated with NF-κB. In particular, the beneficial anti-inflammatory effects of ethyl pyruvate seem to be regulated by the HMGB1/NF-κB axis in the liver, thereby, restraining inflammatory responses and liver injury after double hit trauma in the rat.
MeSH term(s)	Animals ; Female ; HMGB1 Protein/metabolism ; Inflammation/prevention & control ; Liver/drug effects ; Liver/injuries ; NF-kappa B/metabolism ; Pyruvates/pharmacology ; Rats ; Rats, Inbred Lew ; Shock, Hemorrhagic/complications ; Thoracic Injuries/complications ; Wounds, Nonpenetrating/complications
Chemical Substances	HMGB1 Protein ; Hbp1 protein, rat ; NF-kappa B ; Pyruvates ; ethyl pyruvate (03O98E01OB)
Language	English
Publishing date	2018
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.0192171
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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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In stock of ZB MED Cologne/Königswinter

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Inter-library loan at ZB MED

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In stock of ZB MED Cologne/Königswinter

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