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202. Catalyzing Transcriptomics Research in Cardiovascular Disease: The CardioRNA COST Action CA17129

Author

Gomes, Clarissa Pedrosa da C, Ágg, Bence, Andova, Andrejaana, Arslan, Serdal, Baker, Andrew, Barteková, Monika, Beis, Dimitris, Betsou, Fay, Wettinger, Stephanie Bezzina, Bugarski, Branko, Condorelli, Gianluigi, da Silva, Gustavo Jose Justo, Danilin, Sabrina, de Gonzalo-Calvo, David, Buil, Alfonso, Carmo-Fonseca, Maria, Enguita, Francisco J, Felekkis, Kyriacos, Ferdinandy, Peter, Gyöngyösi, Mariann, Hackl, Matthias, Karaduzović-Hadžiabdić, Kanita, Hellemans, Jan, Heymans, Stephane, Hlavackova, Markéta, Hoydal, Morten Andre, Janković, Aleksandra, Jusić, Amela, Kardassis, Dimitris, Kerkelä, Risto, Kuster, Gabriela M, Lakkisto, Päivi, Leszek, Przemyslaw, Lustrek, Mitja, Maegdefessel, Lars, Martelli, Fabio, Novella, Susana, O'Brien, Timothy, Papaneophytou, Christos, Pedrazzini, Thierry, Pinet, Florence, Popescu, Octavian, Potočnjak, Ines, Robinson, Emma, Sasson, Shlomo, Scholz, Markus, Simionescu, Maya, Stoll, Monika, Varga, Zoltan V, Vinciguerra, Manlio, Xuereb, Angela, Yilmaz, Mehmet Birhan, Emanueli, Costanza, Devaux, Yvan, Gomes, Clarissa Pedrosa da C, Ágg, Bence, Andova, Andrejaana, Arslan, Serdal, Baker, Andrew, Barteková, Monika, Beis, Dimitris, Betsou, Fay, Wettinger, Stephanie Bezzina, Bugarski, Branko, Condorelli, Gianluigi, da Silva, Gustavo Jose Justo, Danilin, Sabrina, de Gonzalo-Calvo, David, Buil, Alfonso, Carmo-Fonseca, Maria, Enguita, Francisco J, Felekkis, Kyriacos, Ferdinandy, Peter, Gyöngyösi, Mariann, Hackl, Matthias, Karaduzović-Hadžiabdić, Kanita, Hellemans, Jan, Heymans, Stephane, Hlavackova, Markéta, Hoydal, Morten Andre, Janković, Aleksandra, Jusić, Amela, Kardassis, Dimitris, Kerkelä, Risto, Kuster, Gabriela M, Lakkisto, Päivi, Leszek, Przemyslaw, Lustrek, Mitja, Maegdefessel, Lars, Martelli, Fabio, Novella, Susana, O'Brien, Timothy, Papaneophytou, Christos, Pedrazzini, Thierry, Pinet, Florence, Popescu, Octavian, Potočnjak, Ines, Robinson, Emma, Sasson, Shlomo, Scholz, Markus, Simionescu, Maya, Stoll, Monika, Varga, Zoltan V, Vinciguerra, Manlio, Xuereb, Angela, Yilmaz, Mehmet Birhan, Emanueli, Costanza, and Devaux, Yvan

Abstract

Cardiovascular disease (CVD) remains the leading cause of death worldwide and, despite continuous advances, better diagnostic and prognostic tools, as well as therapy, are needed. The human transcriptome, which is the set of all RNA produced in a cell, is much more complex than previously thought and the lack of dialogue between researchers and industrials and consensus on guidelines to generate data make it harder to compare and reproduce results. This European Cooperation in Science and Technology (COST) Action aims to accelerate the understanding of transcriptomics in CVD and further the translation of experimental data into usable applications to improve personalized medicine in this field by creating an interdisciplinary network. It aims to provide opportunities for collaboration between stakeholders from complementary backgrounds, allowing the functions of different RNAs and their interactions to be more rapidly deciphered in the cardiovascular context for translation into the clinic, thus fostering personalized medicine and meeting a current public health challenge. Thus, this Action will advance studies on cardiovascular transcriptomics, generate innovative projects, and consolidate the leadership of European research groups in the field. COST (European Cooperation in Science and Technology) is a funding organization for research and innovation networks (www.cost.eu).

Published
2019

203. Catalyzing transcriptomics research in cardiovascular disease: the CardioRNA COST action CA17129

Author

European Cooperation in Science and Technology, Pedrosa da Costa Gomes, Clarissa, Ágg, Bence, Andova, Andrejaana, Arslan, Serdal, Baker, Andrew, Barteková, Monika, Beis, Dimitris, Betsou, Fay, Bezzina Wettinger, Stephanie, Bugarski, Branko, Condorelli, Gianluigi, Silva, Gustavo José Justo da, Danilin, Sabrina, Gonzalo-Calvo, David de, Buil, Alfonso, Carmo-Fonseca, Maria, Enguita, Francisco J., Felekkis, Kyriacos, Ferdinandy, Peter, Gyöngyösi, Mariann, Hackl, Matthias, Karaduzovic-Hadziabdic, Kanita, Hellemans, Jan, Heymans, Stephane, Hlavackova, Markéta, Hoydal, Morten Andre, Jankovic, Aleksandra, Jusic, Amela, Kardassis, Dimitris, Kerkelä, Risto, Kuster, Gabriela M., Lakkisto, Päivi, Leszek, Przemyslaw, Lustrek, Mitja, Maegdefessel, Lars, Martelli, Fabio, Novella, Susana, O’Brien, Timothy, Papaneophytou, Christos, Pedrazzini, Thierry, Pinet, Florence, Popescu, Octavian, Potočnjak, Ines, Robinson, Emma, Sasson, Shlomo, Scholz, Markus, Simionescu, Maya, Stoll, Monika, Varga, Zoltan V., Vinciguerra, Manlio, Xuereb, Angela, Yilmaz, Mehmet Birhan, Emanueli, Costanza, Devaux, Yvan, European Cooperation in Science and Technology, Pedrosa da Costa Gomes, Clarissa, Ágg, Bence, Andova, Andrejaana, Arslan, Serdal, Baker, Andrew, Barteková, Monika, Beis, Dimitris, Betsou, Fay, Bezzina Wettinger, Stephanie, Bugarski, Branko, Condorelli, Gianluigi, Silva, Gustavo José Justo da, Danilin, Sabrina, Gonzalo-Calvo, David de, Buil, Alfonso, Carmo-Fonseca, Maria, Enguita, Francisco J., Felekkis, Kyriacos, Ferdinandy, Peter, Gyöngyösi, Mariann, Hackl, Matthias, Karaduzovic-Hadziabdic, Kanita, Hellemans, Jan, Heymans, Stephane, Hlavackova, Markéta, Hoydal, Morten Andre, Jankovic, Aleksandra, Jusic, Amela, Kardassis, Dimitris, Kerkelä, Risto, Kuster, Gabriela M., Lakkisto, Päivi, Leszek, Przemyslaw, Lustrek, Mitja, Maegdefessel, Lars, Martelli, Fabio, Novella, Susana, O’Brien, Timothy, Papaneophytou, Christos, Pedrazzini, Thierry, Pinet, Florence, Popescu, Octavian, Potočnjak, Ines, Robinson, Emma, Sasson, Shlomo, Scholz, Markus, Simionescu, Maya, Stoll, Monika, Varga, Zoltan V., Vinciguerra, Manlio, Xuereb, Angela, Yilmaz, Mehmet Birhan, Emanueli, Costanza, and Devaux, Yvan

Abstract

Cardiovascular disease (CVD) remains the leading cause of death worldwide and, despite continuous advances, better diagnostic and prognostic tools, as well as therapy, are needed. The human transcriptome, which is the set of all RNA produced in a cell, is much more complex than previously thought and the lack of dialogue between researchers and industrials and consensus on guidelines to generate data make it harder to compare and reproduce results. This European Cooperation in Science and Technology (COST) Action aims to accelerate the understanding of transcriptomics in CVD and further the translation of experimental data into usable applications to improve personalized medicine in this field by creating an interdisciplinary network. It aims to provide opportunities for collaboration between stakeholders from complementary backgrounds, allowing the functions of different RNAs and their interactions to be more rapidly deciphered in the cardiovascular context for translation into the clinic, thus fostering personalized medicine and meeting a current public health challenge. Thus, this Action will advance studies on cardiovascular transcriptomics, generate innovative projects, and consolidate the leadership of European research groups in the field. COST (European Cooperation in Science and Technology) is a funding organization for research and innovation networks (www.cost.eu).

Published
2019

204. Cyclin-dependent kinase inhibitor 2B regulates efferocytosis and atherosclerosis

Author

Kojima, Yoko, Downing, Kelly, Kundu, Ramendra, Miller, Clint, Dewey, Frederick, Lancero, Hope, Raaz, Uwe, Perisic, Ljubica, Hedin, Ulf, Schadt, Eric, Maegdefessel, Lars, Quertermous, Tom, and Leeper, Nicholas J.

Subjects
Health care industry
Abstract

During the assembly of Figure 6A and Supplemental Figure 4C, incorrect flow cytometry plots were included. The authors were able to provide the original data, and a corrected version of [...]

Published
2019
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206. Correlation of computed tomography with carotid plaque transcriptomes associates calcification with lesion-stabilization

Author

Karlöf, Eva, primary, Seime, Till, additional, Dias, Nuno, additional, Lengquist, Mariette, additional, Witasp, Anna, additional, Almqvist, Håkan, additional, Kronqvist, Malin, additional, Gådin, Jesper R., additional, Odeberg, Jacob, additional, Maegdefessel, Lars, additional, Stenvinkel, Peter, additional, Matic, Ljubica Perisic, additional, and Hedin, Ulf, additional

Published
2019
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209. Externalized histone H4 orchestrates chronic inflammation by inducing lytic cell death

Author

Silvestre-Roig, Carlos, primary, Braster, Quinte, additional, Wichapong, Kanin, additional, Lee, Ernest Y., additional, Teulon, Jean Marie, additional, Berrebeh, Nihel, additional, Winter, Janine, additional, Adrover, José M., additional, Santos, Giancarlo Santiago, additional, Froese, Alexander, additional, Lemnitzer, Patricia, additional, Ortega-Gómez, Almudena, additional, Chevre, Raphael, additional, Marschner, Julian, additional, Schumski, Ariane, additional, Winter, Carla, additional, Perez-Olivares, Laura, additional, Pan, Chang, additional, Paulin, Nicole, additional, Schoufour, Tom, additional, Hartwig, Helene, additional, González-Ramos, Silvia, additional, Kamp, Frits, additional, Megens, Remco T. A., additional, Mowen, Kerri A., additional, Gunzer, Matthias, additional, Maegdefessel, Lars, additional, Hackeng, Tilman, additional, Lutgens, Esther, additional, Daemen, Mat, additional, von Blume, Julia, additional, Anders, Hans-Joachim, additional, Nikolaev, Viacheslav O., additional, Pellequer, Jean-Luc, additional, Weber, Christian, additional, Hidalgo, Andrés, additional, Nicolaes, Gerry A. F., additional, Wong, Gerard C. L., additional, and Soehnlein, Oliver, additional

Published
2019
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211. Dual roles of heparanase in human carotid plaque calcification

Author

Aldi, Silvia, primary, Eriksson, Linnéa, additional, Kronqvist, Malin, additional, Lengquist, Mariette, additional, Löfling, Marie, additional, Folkersen, Lasse, additional, Matic, Ljubica P., additional, Maegdefessel, Lars, additional, Grinnemo, Karl-Henrik, additional, Li, Jin-Ping, additional, Österholm, C., additional, and Hedin, Ulf, additional

Published
2019
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212. Catalyzing Transcriptomics Research in Cardiovascular Disease: The CardioRNA COST Action CA17129

Author

Gomes, Clarissa, primary, Ágg, Bence, additional, Andova, Andrejaana, additional, Arslan, Serdal, additional, Baker, Andrew, additional, Barteková, Monika, additional, Beis, Dimitris, additional, Betsou, Fay, additional, Wettinger, Stephanie, additional, Bugarski, Branko, additional, Condorelli, Gianluigi, additional, Silva, Gustavo, additional, Danilin, Sabrina, additional, Gonzalo-Calvo, David, additional, Buil, Alfonso, additional, Carmo-Fonseca, Maria, additional, Enguita, Francisco, additional, Felekkis, Kyriacos, additional, Ferdinandy, Peter, additional, Gyöngyösi, Mariann, additional, Hackl, Matthias, additional, Karaduzovic-Hadziabdic, Kanita, additional, Hellemans, Jan, additional, Heymans, Stephane, additional, Hlavackova, Markéta, additional, Hoydal, Morten, additional, Jankovic, Aleksandra, additional, Jusic, Amela, additional, Kardassis, Dimitris, additional, Kerkelä, Risto, additional, Kuster, Gabriela, additional, Lakkisto, Päivi, additional, Leszek, Przemyslaw, additional, Lustrek, Mitja, additional, Maegdefessel, Lars, additional, Martelli, Fabio, additional, Novella, Susana, additional, O’Brien, Timothy, additional, Papaneophytou, Christos, additional, Pedrazzini, Thierry, additional, Pinet, Florence, additional, Popescu, Octavian, additional, Potočnjak, Ines, additional, Robinson, Emma, additional, Sasson, Shlomo, additional, Scholz, Markus, additional, Simionescu, Maya, additional, Stoll, Monika, additional, Varga, Zoltan, additional, Vinciguerra, Manlio, additional, Xuereb, Angela, additional, Yilmaz, Mehmet, additional, Emanueli, Costanza, additional, Devaux, Yvan, additional, and EU-CardioRNA COST Action (CAonesevenonetwonine), on behalf of the, additional

Published
2019
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213. Hematopoietic Deficiency of the Long Noncoding RNA MALAT1 Promotes Atherosclerosis and Plaque Inflammation

Author

Cremer, Sebastian, primary, Michalik, Katharina M., additional, Fischer, Ariane, additional, Pfisterer, Larissa, additional, Jaé, Nicolas, additional, Winter, Carla, additional, Boon, Reinier A., additional, Muhly-Reinholz, Marion, additional, John, David, additional, Uchida, Shizuka, additional, Weber, Christian, additional, Poller, Wolfgang, additional, Günther, Stefan, additional, Braun, Thomas, additional, Li, Daniel Y., additional, Maegdefessel, Lars, additional, Perisic Matic, Ljubica, additional, Hedin, Ulf, additional, Soehnlein, Oliver, additional, Zeiher, Andreas, additional, and Dimmeler, Stefanie, additional

Published
2019
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215. Biobanking: Objectives, Requirements, and Future Challenges—Experiences from the Munich Vascular Biobank

Author

Pelisek, Jaroslav, primary, Hegenloh, Renate, additional, Bauer, Sabine, additional, Metschl, Susanne, additional, Pauli, Jessica, additional, Glukha, Nadiya, additional, Busch, Albert, additional, Reutersberg, Benedikt, additional, Kallmayer, Michael, additional, Trenner, Matthias, additional, Wendorff, Heiko, additional, Tsantilas, Pavlos, additional, Schmid, Sofie, additional, Knappich, Christoph, additional, Schaeffer, Christoph, additional, Stadlbauer, Thomas, additional, Biro, Gabor, additional, Wertern, Uta, additional, Meisner, Franz, additional, Stoklasa, Kerstin, additional, Menges, Anna-Leonie, additional, Radu, Oksana, additional, Dallmann-Sieber, Sabine, additional, Karlas, Angelos, additional, Knipfer, Eva, additional, Reeps, Christian, additional, Zimmermann, Alexander, additional, Maegdefessel, Lars, additional, and Eckstein, Hans-Henning, additional

Published
2019
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218. miR-29b Mediates the Chronic Inflammatory Response in Radiotherapy-Induced Vascular Disease

Author

Eken, Suzanne M., primary, Christersdottir, Tinna, additional, Winski, Greg, additional, Sangsuwan, Traimate, additional, Jin, Hong, additional, Chernogubova, Ekaterina, additional, Pirault, John, additional, Sun, Changyan, additional, Simon, Nancy, additional, Winter, Hanna, additional, Backlund, Alexandra, additional, Haghdoost, Siamak, additional, Hansson, Göran K., additional, Halle, Martin, additional, and Maegdefessel, Lars, additional

Published
2019
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220. The long noncoding RNA CHROME regulates cholesterol homeostasis in primates

Author

Hennessy, Elizabeth J., primary, van Solingen, Coen, additional, Scacalossi, Kaitlyn R., additional, Ouimet, Mireille, additional, Afonso, Milessa S., additional, Prins, Jurrien, additional, Koelwyn, Graeme J., additional, Sharma, Monika, additional, Ramkhelawon, Bhama, additional, Carpenter, Susan, additional, Busch, Albert, additional, Chernogubova, Ekaterina, additional, Matic, Ljubica Perisic, additional, Hedin, Ulf, additional, Maegdefessel, Lars, additional, Caffrey, Brian E., additional, Hussein, Maryem A., additional, Ricci, Emiliano P., additional, Temel, Ryan E., additional, Garabedian, Michael J., additional, Berger, Jeffrey S., additional, Vickers, Kasey C., additional, Kanke, Matthew, additional, Sethupathy, Praveen, additional, Teupser, Daniel, additional, Holdt, Lesca M., additional, and Moore, Kathryn J., additional

Published
2018
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221. Guidelines for the functional annotation of microRNAs using the Gene Ontology

Author

Huntley, Rachael P., Sitnikov, Dmitry, Orlic-Milacic, Marija, Balakrishnan, Rama, D'Eustachio, Peter, Gillespie, Marc E., Howe, Doug, Kalea, Anastasia Z., Maegdefessel, Lars, Osumi-Sutherland, David, Petri, Victoria, Smith, Jennifer R., Van Auken, Kimberly, Wood, Valerie, Zampetaki, Anna, Mayr, Manuel, Lovering, Ruth C., Huntley, Rachael P [0000-0001-6718-3559], Sitnikov, Dmitry [0000-0002-5283-5283], Orlic-Milacic, Marija [0000-0002-3218-5631], Balakrishnan, Rama [0000-0003-2468-9933], Gillespie, Marc E [0000-0002-5766-1702], Howe, Doug [0000-0001-5831-7439], Kalea, Anastasia Z [0000-0001-5775-3984], Maegdefessel, Lars [0000-0001-5228-2634], Osumi-Sutherland, David [0000-0002-7073-9172], Petri, Victoria [0000-0002-5540-8498], Van Auken, Kimberly [0000-0002-1706-4196], Wood, Valerie [0000-0001-6330-7526], Mayr, Manuel [0000-0002-0597-829X], Lovering, Ruth C [0000-0002-9791-0064], and Apollo - University of Cambridge Repository

Subjects
function, microRNA, analysis, biocuration, Annotation, Guidelines as Topic, MicroRNA, Biocuration, Mice, MicroRNAs, annotation, GO, Animals, Humans, Gene Silencing, Function, Analysis
Abstract

MicroRNA regulation of developmental and cellular processes is a relatively new field of study, and the available research data have not been organized to enable its inclusion in pathway and network analysis tools. The association of gene products with terms from the Gene Ontology is an effective method to analyze functional data, but until recently there has been no substantial effort dedicated to applying Gene Ontology terms to microRNAs. Consequently, when performing functional analysis of microRNA data sets, researchers have had to rely instead on the functional annotations associated with the genes encoding microRNA targets. In consultation with experts in the field of microRNA research, we have created comprehensive recommendations for the Gene Ontology curation of microRNAs. This curation manual will enable provision of a high-quality, reliable set of functional annotations for the advancement of microRNA research. Here we describe the key aspects of the work, including development of the Gene Ontology to represent this data, standards for describing the data, and guidelines to support curators making these annotations. The full microRNA curation guidelines are available on the GO Consortium wiki (http://wiki.geneontology.org/index.php/MicroRNA-GO-annotation-manual).

Published
2016

222. H19 Induces Abdominal Aortic Aneurysm Development and Progression

Author

Li, Daniel Y., Busch, Albert, Jin, Hong, Chernogubova, Ekaterina, Pelisek, Jaroslav, Karlsson, Joakim, Sennblad, Bengt, Liu, Shengliang, Lao, Shen, Hofmann, Patrick, Baecklund, Alexandra, Eken, Suzanne M., Roy, Joy, Eriksson, Per, Dacken, Brian, Ramanujam, Deepak, Dueck, Anne, Engelhardt, Stefan, Boon, Reinier A., Eckstein, Hans-Henning, Spin, Joshua M., Tsao, Philip S., Maegdefessel, Lars, Li, Daniel Y., Busch, Albert, Jin, Hong, Chernogubova, Ekaterina, Pelisek, Jaroslav, Karlsson, Joakim, Sennblad, Bengt, Liu, Shengliang, Lao, Shen, Hofmann, Patrick, Baecklund, Alexandra, Eken, Suzanne M., Roy, Joy, Eriksson, Per, Dacken, Brian, Ramanujam, Deepak, Dueck, Anne, Engelhardt, Stefan, Boon, Reinier A., Eckstein, Hans-Henning, Spin, Joshua M., Tsao, Philip S., and Maegdefessel, Lars

Abstract

Background: Long noncoding RNAs have emerged as critical molecular regulators in various biological processes and diseases. Here we sought to identify and functionally characterize long noncoding RNAs as potential mediators in abdominal aortic aneurysm development. Methods: We profiled RNA transcript expression in 2 murine abdominal aortic aneurysm models, Angiotensin II (ANGII) infusion in apolipoprotein E-deficient (ApoE(-/-)) mice (n=8) and porcine pancreatic elastase instillation in C57BL/6 wild-type mice (n=12). The long noncoding RNA H19 was identified as 1 of the most highly upregulated transcripts in both mouse aneurysm models compared with sham-operated controls. This was confirmed by quantitative reverse transcription-polymerase chain reaction and in situ hybridization. Results: Experimental knock-down of H19, utilizing site-specific antisense oligonucleotides (LNA-GapmeRs) in vivo, significantly limited aneurysm growth in both models. Upregulated H19 correlated with smooth muscle cell (SMC) content and SMC apoptosis in progressing aneurysms. Importantly, a similar pattern could be observed in human abdominal aortic aneurysm tissue samples, and in a novel preclinical LDLR-/- (low-density lipoprotein receptor) Yucatan mini-pig aneurysm model. In vitro knock-down of H19 markedly decreased apoptotic rates of cultured human aortic SMCs, whereas overexpression of H19 had the opposite effect. Notably, H19-dependent apoptosis mechanisms in SMCs appeared to be independent of miR-675, which is embedded in the first exon of the H19 gene. A customized transcription factor array identified hypoxia-inducible factor 1 as the main downstream effector. Increased SMC apoptosis was associated with cytoplasmic interaction between H19 and hypoxia-inducible factor 1 and sequential p53 stabilization. Additionally, H19 induced transcription of hypoxia-inducible factor 1 via recruiting the transcription factor specificity protein 1 to the promoter region. Conclusions: The long no

Published
2018
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223. Cysteinyl leukotriene receptor 1 antagonism prevents experimental abdominal aortic aneurysm

Author

Di Gennaro, Antonio, Araujo, Ana Carolina, Busch, Albert, Jin, Hong, Wågsäter, Dick, Vorkapic, Emina, Caidahl, Kenneth, Eriksson, Per, Samuelsson, Bengt, Maegdefessel, Lars, Haeggstrom, Jesper Z., Di Gennaro, Antonio, Araujo, Ana Carolina, Busch, Albert, Jin, Hong, Wågsäter, Dick, Vorkapic, Emina, Caidahl, Kenneth, Eriksson, Per, Samuelsson, Bengt, Maegdefessel, Lars, and Haeggstrom, Jesper Z.

Abstract

Cysteinyl-leukotrienes (cys-LTs) are 5-lipoxygenase-derived lipid mediators involved in the pathogenesis and progression of inflammatory disorders, in particular asthma. We have previously found evidence linking these mediators to increased levels of proteolytic enzymes in tissue specimens of human abdominal aortic aneurysm (AAA). Here we show that antagonism of the CysLT1 receptor by montelukast, an established antiasthma drug, protects against a strong aorta dilatation (amp;gt;50% increase = aneurysm) in a mouse model of CaCl2-induced AAA at a dose comparable to human medical practice. Analysis of tissue extracts revealed that montelukast reduces the levels of matrix metalloproteinase-9 (MMP-9) and macrophage inflammatory protein-1 alpha (MIP-1 alpha) in the aortic wall. Furthermore, aneurysm progression was specifically mediated through CysLT1 signaling since a selective CysLT2 antagonist was without effect. A significantly reduced vessel dilatation is also observed when treatment with montelukast is started days after aneurysm induction, suggesting that the drug not only prevents but also stops and possibly reverts an already ongoing degenerative process. Moreover, montelukast reduced the incidence of aortic rupture and attenuated the AAA development in two additional independent models, i.e., angiotensin II- and porcine pancreatic elastase-induced AAA, respectively. Our results indicate that cys-LTs are involved in the pathogenesis of AAA and that antagonism of the CysLT1 receptor is a promising strategy for preventive and therapeutic treatment of this clinically silent and highly lethal disease., Funding Agencies|Swedish Research Council [10350]; Stockholm County Council [20150517]; Linneus Grant Center of Excellence for Research on Inflammation and Cardiovascular Disease, Novo Nordisk Foundation [NNF15CC0018346, NNF15CC0018486]; Cardiovascular Program (CVP); Swedish Heart Lung Foundation [20120615, 20130664, 20140186, 20150423]; Ragnar Soderberg Foundation [M-14/55]; Karolinska Institutet CVP Career Development Grant; European Research Council (Starting Grant NORVAS); Karolinska Institutet

Published
2018
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225. Functional investigation of the coronary artery disease gene SVEP1.

Author

Winkler, Michael J., Müller, Philipp, Sharifi, Amin M., Wobst, Jana, Winter, Hanna, Mokry, Michal, Ma, Lijiang, van der Laan, Sander W., Pang, Shichao, Miritsch, Benedikt, Hinterdobler, Julia, Werner, Julia, Stiller, Barbara, Güldener, Ulrich, Webb, Tom R., Asselbergs, Folkert W., Björkegren, Johan L. M., Maegdefessel, Lars, Schunkert, Heribert, and Sager, Hendrik B.

Abstract

A missense variant of the sushi, von Willebrand factor type A, EGF and pentraxin domain containing protein 1 (SVEP1) is genome-wide significantly associated with coronary artery disease. The mechanisms how SVEP1 impacts atherosclerosis are not known. We found endothelial cells (EC) and vascular smooth muscle cells to represent the major cellular source of SVEP1 in plaques. Plaques were larger in atherosclerosis-prone Svep1 haploinsufficient (ApoE−/−Svep1+/−) compared to Svep1 wild-type mice (ApoE−/−Svep1+/+) and ApoE−/−Svep1+/− mice displayed elevated plaque neutrophil, Ly6Chigh monocyte, and macrophage numbers. We assessed how leukocytes accumulated more inside plaques in ApoE−/−Svep1+/− mice and found enhanced leukocyte recruitment from blood into plaques. In vitro, we examined how SVEP1 deficiency promotes leukocyte recruitment and found elevated expression of the leukocyte attractant chemokine (C-X-C motif) ligand 1 (CXCL1) in EC after incubation with missense compared to wild-type SVEP1. Increasing wild-type SVEP1 levels silenced endothelial CXCL1 release. In line, plasma Cxcl1 levels were elevated in ApoE−/−Svep1+/− mice. Our studies reveal an atheroprotective role of SVEP1. Deficiency of wild-type Svep1 increased endothelial CXCL1 expression leading to enhanced recruitment of proinflammatory leukocytes from blood to plaque. Consequently, elevated vascular inflammation resulted in enhanced plaque progression in Svep1 deficiency. [ABSTRACT FROM AUTHOR]

Published
2020
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226. Utilization of an Artery‐on‐a‐Chip to Unravel Novel Regulators and Therapeutic Targets in Vascular Diseases

Author

Paloschi, Valentina, Pauli, Jessica, Winski, Greg, Wu, Zhiyuan, Li, Zhaolong, Botti, Lorenzo, Meucci, Sandro, Conti, Pierangelo, Rogowitz, Felix, Glukha, Nadiya, Hummel, Nora, Busch, Albert, Chernogubova, Ekaterina, Jin, Hong, Sachs, Nadja, Eckstein, Hans‐Henning, Dueck, Anne, Boon, Reinier A., Bausch, Andreas R., and Maegdefessel, Lars

Abstract

In this study, organ‐on‐chip technology is used to develop an in vitro model of medium‐to‐large size arteries, the artery‐on‐a‐chip (AoC), with the objective to recapitulate the structure of the arterial wall and the relevant hemodynamic forces affecting luminal cells. AoCs exposed either to in vivo‐like shear stress values or kept in static conditions are assessed to generate a panel of novel genes modulated by shear stress. Considering the crucial role played by shear stress alterations in carotid arteries affected by atherosclerosis (CAD) and abdominal aortic aneurysms (AAA) disease development/progression, a patient cohort of hemodynamically relevant specimens is utilized, consisting of diseased and non‐diseased (internal control) vessel regions from the same patient. Genes activated by shear stress follow the same expression pattern in non‐diseased segments of human vessels. Single cell RNA sequencing (scRNA‐seq) enables to discriminate the unique cell subpopulations between non‐diseased and diseased vessel portions, revealing an enrichment of flow activated genes in structural cells originating from non‐diseased specimens. Furthermore, the AoC served as a platform for drug‐testing. It reproduced the effects of a therapeutic agent (lenvatinib) previously used in preclinical AAA studies, therefore extending the understanding of its therapeutic effect through a multicellular structure. The artery‐on‐a‐chip (AoC) in vitro model is capable of mimicking important physiological aspects of human arteries, such as the response to shear stress, and can further shed light on the mechanism of action of potential therapeutics before they enter the clinical stage.

Published
2024
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227. Clonally expanding smooth muscle cells promote atherosclerosis by escaping efferocytosis and activating the complement cascade.

Author

Ying Wang, Nanda, Vivek, Direnzo, Daniel, Jianqin Ye, Sophia Xiao, Yoko Kojima, Howe, Kathryn L., Jarr, Kai-Uwe, Flores, Alyssa M., Tsantilas, Pavlos, Noah Tsao, Rao, Abhiram, Newman, Alexandra A. C., Eberhard, Anne V., Priest, James R., Ruusalepp, Arno, Pasterkamp, Gerard, Maegdefessel, Lars, Miller, Clint L., and Lind, Lars

Subjects
MUSCLE cells, SMOOTH muscle, VASCULAR smooth muscle, ATHEROSCLEROSIS, ATHEROSCLEROTIC plaque
Abstract

Atherosclerosis is the process underlying heart attack and stroke. Despite decades of research, its pathogenesis remains unclear. Dogma suggests that atherosclerotic plaques expand primarily via the accumulation of cholesterol and inflammatory cells. However, recent evidence suggests that a substantial portion of the plaque may arise from a subset of “dedifferentiated” vascular smooth muscle cells (SMCs) which proliferate in a clonal fashion. Herein we use multicolor lineage-tracing models to confirm that the matureSMCcangive riseto a hyperproliferativecellwhich appearsto promote inflammation via elaboration of complement-dependent anaphylatoxins. Despite being extensively opsonized with prophagocytic complement fragments, we find that this cell also escapes immune surveillance by neighboring macrophages, thereby exacerbating its relative survival advantage. Mechanistic studies indicate this phenomenon results from a generalized opsoninsensing defect acquired by macrophages during polarization. This defect coincides with the noncanonical up-regulation of so-called don’t eat me molecules on inflamed phagocytes, which reduces their capacity for programmed cell removal (PrCR). Knockdown or knockout of the key antiphagocytic molecule CD47 restores the ability of macrophages to sense and clear opsonized targets in vitro, allowing for potent and targeted suppression of clonal SMC expansion in the plaque in vivo. Because integrated clinical and genomic analyses indicate that similar pathways are active in humans with cardiovascular disease, these studies suggest that the clonally expanding SMC may represent a translational target for treating atherosclerosis. [ABSTRACT FROM AUTHOR]

Published
2020
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231. H19 Induces Abdominal Aortic Aneurysm Development and Progression

Author

Li, Daniel Y., primary, Busch, Albert, additional, Jin, Hong, additional, Chernogubova, Ekaterina, additional, Pelisek, Jaroslav, additional, Karlsson, Joakim, additional, Sennblad, Bengt, additional, Liu, Shengliang, additional, Lao, Shen, additional, Hofmann, Patrick, additional, Bäcklund, Alexandra, additional, Eken, Suzanne M., additional, Roy, Joy, additional, Eriksson, Per, additional, Dacken, Brian, additional, Ramanujam, Deepak, additional, Dueck, Anne, additional, Engelhardt, Stefan, additional, Boon, Reinier A., additional, Eckstein, Hans-Henning, additional, Spin, Joshua M., additional, Tsao, Philip S., additional, and Maegdefessel, Lars, additional

Published
2018
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237. Therapeutically Targeting the Kinase Activity or Gene Expression of RIP1 Reduces Inflammation-driven Atherosclerosis and Promotes Plaque Stability

Author

Karunakaran, Denuja, primary, Geoffrion, Michele, additional, Wei, Lihui, additional, Gan, Wei, additional, Perisic, Ljubica, additional, Maegdefessel, Lars, additional, Hedin, Ulf, additional, Sad, Subash, additional, Guo, Liang, additional, Kolodgie, Frank, additional, Ruddy, Terrence, additional, Virmani, Renu, additional, and Rayner, Katey, additional

Published
2018
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243. Abstract 454: Repression of Map1lc3a During Atherosclerosis Progression Plays an Important Role in the Regulation of Vascular Smooth Muscle Cell Phenotype

Author

Magné, Joelle, primary, Paloschi, Valentina, additional, Gonçalves, Isabel, additional, Saliba-Gustafsson, Peter, additional, Skogsberg, Josefin, additional, Razuvaev, Anton, additional, Jin, Hong, additional, Li, Yuhuang, additional, Ketelhuth, Daniel F.J., additional, Maegdefessel, Lars, additional, Hedin, Ulf, additional, Eriksson, Per, additional, and Ehrenborg, Ewa, additional

Published
2018
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245. Abstract 652: MicroRNA-29b Mediates the Chronic Inflammatory Response in Radiotherapy-induced Vascular Disease

Author

Winski, Greg, primary, Eken, Suzanne M, additional, Christersdottir, Tinna, additional, Sangsuwan, Traimate, additional, Jin, Hong, additional, Chernogubova, Ekaterina, additional, Pirault, John, additional, Sun, Changyan, additional, Simon, Nancy, additional, Winter, Hanna, additional, Tornvall, Per, additional, Haghdoost, Siamak, additional, Hansson, Göran K, additional, Halle, Martin, additional, and Maegdefessel, Lars, additional

Published
2018
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248. Local Delivery of miR-21 Stabilizes Fibrous Caps in Vulnerable Atherosclerotic Lesions

Author

Jin, Hong, primary, Li, Daniel Y., additional, Chernogubova, Ekaterina, additional, Sun, Changyan, additional, Busch, Albert, additional, Eken, Suzanne M., additional, Saliba-Gustafsson, Peter, additional, Winter, Hanna, additional, Winski, Greg, additional, Raaz, Uwe, additional, Schellinger, Isabel N., additional, Simon, Nancy, additional, Hegenloh, Renate, additional, Matic, Ljubica Perisic, additional, Jagodic, Maja, additional, Ehrenborg, Ewa, additional, Pelisek, Jaroslav, additional, Eckstein, Hans-Henning, additional, Hedin, Ulf, additional, Backlund, Alexandra, additional, and Maegdefessel, Lars, additional

Published
2018
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