Browsing by Author "Kessler, Thorsten"

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    Acute mental stress drives vascular inflammation and promotes plaque destabilization in mouse atherosclerosis
    (2021-10-14) Hinterdobler, Julia; Schott, Simin S.; Jin, Hong; Meesmann, Almut; Steinsiek, Anna Lena; Zimmermann, Anna Sophia; Wobst, Jana; Müller, Philipp; Mauersberger, Carina; Vilne, Baiba; Baecklund, Alexandra; Chen, Chien Sin; Moggio, Aldo; Braster, Quinte; Molitor, Michael; Krane, Markus; Kempf, Wolfgang E.; Ladwig, Karl Heinz; Hristov, Michael; Hulsmans, Maarten; Hilgendorf, Ingo; Weber, Christian; Wenzel, Philip; Scheiermann, Christoph; Maegdefessel, Lars; Soehnlein, Oliver; Libby, Peter; Nahrendorf, Matthias; Schunkert, Heribert; Kessler, Thorsten; Sager, Hendrik B.; Rīga Stradiņš University
    Aims: Mental stress substantially contributes to the initiation and progression of human disease, including cardiovascular conditions. We aim to investigate the underlying mechanisms of these contributions since they remain largely unclear. Methods and results: Here, we show in humans and mice that leucocytes deplete rapidly from the blood after a single episode of acute mental stress. Using cell-tracking experiments in animal models of acute mental stress, we found that stress exposure leads to prompt uptake of inflammatory leucocytes from the blood to distinct tissues including heart, lung, skin, and, if present, atherosclerotic plaques. Mechanistically, we found that acute stress enhances leucocyte influx into mouse atherosclerotic plaques by modulating endothelial cells. Specifically, acute stress increases adhesion molecule expression and chemokine release through locally derived norepinephrine. Either chemical or surgical disruption of norepinephrine signalling diminished stress-induced leucocyte migration into mouse atherosclerotic plaques. Conclusion: Our data show that acute mental stress rapidly amplifies inflammatory leucocyte expansion inside mouse atherosclerotic lesions and promotes plaque vulnerability.
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    The impact of genome-wide association studies on the pathophysiology and therapy of cardiovascular disease
    (2016-07-01) Kessler, Thorsten; Vilne, Baiba; Schunkert, Heribert
    Cardiovascular diseases are leading causes for death worldwide. Genetic disposition jointly with traditional risk factors precipitates their manifestation. Whereas the implications of a positive family history for individual risk have been known for a long time, only in the past few years have genome-wide association studies (GWAS) shed light on the underlying genetic variations. Here, we review these studies designed to increase our understanding of the pathophysiology of cardiovascular diseases, particularly coronary artery disease and myocardial infarction. We focus on the newly established pathways to exemplify the translation from the identification of risk-related genetic variants to new preventive and therapeutic strategies for cardiovascular disease.
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    Network analysis of coronary artery disease risk genes elucidates disease mechanisms and druggable targets
    (2018-12-01) Lempiäinen, Harri; Brænne, Ingrid; Michoel, Tom; Tragante, Vinicius; Vilne, Baiba; Webb, Tom R.; Kyriakou, Theodosios; Eichner, Johannes; Zeng, Lingyao; Willenborg, Christina; Franzen, Oscar; Ruusalepp, Arno; Goel, Anuj; Van Der Laan, Sander W.; Biegert, Claudia; Hamby, Stephen; Talukdar, Husain A.; Foroughi Asl, Hassan; Dichgans, Martin; Dreker, Tobias; Graettinger, Mira; Gribbon, Philip; Kessler, Thorsten; Malik, Rainer; Prestel, Matthias; Stiller, Barbara; Schofield, Christine; Pasterkamp, Gerard; Watkins, Hugh; Samani, Nilesh J.; Wittenberger, Timo; Erdmann, Jeanette; Schunkert, Heribert; Asselbergs, Folkert W.; Björkegren, Johan L.M.
    Genome-wide association studies (GWAS) have identified over two hundred chromosomal loci that modulate risk of coronary artery disease (CAD). The genes affected by variants at these loci are largely unknown and an untapped resource to improve our understanding of CAD pathophysiology and identify potential therapeutic targets. Here, we prioritized 68 genes as the most likely causal genes at genome-wide significant loci identified by GWAS of CAD and examined their regulatory roles in 286 metabolic and vascular tissue gene-protein sub-networks ("modules"). The modules and genes within were scored for CAD druggability potential. The scoring enriched for targets of cardiometabolic drugs currently in clinical use and in-depth analysis of the top-scoring modules validated established and revealed novel target tissues, biological processes, and druggable targets. This study provides an unprecedented resource of tissue-defined gene-protein interactions directly affected by genetic variance in CAD risk loci.
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    Network analysis of coronary artery disease risk genes elucidates disease mechanisms and druggable targets
    (2018-12-01) Lempiäinen, Harri; Brænne, Ingrid; Michoel, Tom; Tragante, Vinicius; Vilne, Baiba; Webb, Tom R.; Kyriakou, Theodosios; Eichner, Johannes; Zeng, Lingyao; Willenborg, Christina; Franzen, Oscar; Ruusalepp, Arno; Goel, Anuj; Van Der Laan, Sander W.; Biegert, Claudia; Hamby, Stephen; Talukdar, Husain A.; Foroughi Asl, Hassan; Dichgans, Martin; Dreker, Tobias; Graettinger, Mira; Gribbon, Philip; Kessler, Thorsten; Malik, Rainer; Prestel, Matthias; Stiller, Barbara; Schofield, Christine; Pasterkamp, Gerard; Watkins, Hugh; Samani, Nilesh J.; Wittenberger, Timo; Erdmann, Jeanette; Schunkert, Heribert; Asselbergs, Folkert W.; Björkegren, Johan L.M.
    Genome-wide association studies (GWAS) have identified over two hundred chromosomal loci that modulate risk of coronary artery disease (CAD). The genes affected by variants at these loci are largely unknown and an untapped resource to improve our understanding of CAD pathophysiology and identify potential therapeutic targets. Here, we prioritized 68 genes as the most likely causal genes at genome-wide significant loci identified by GWAS of CAD and examined their regulatory roles in 286 metabolic and vascular tissue gene-protein sub-networks ("modules"). The modules and genes within were scored for CAD druggability potential. The scoring enriched for targets of cardiometabolic drugs currently in clinical use and in-depth analysis of the top-scoring modules validated established and revealed novel target tissues, biological processes, and druggable targets. This study provides an unprecedented resource of tissue-defined gene-protein interactions directly affected by genetic variance in CAD risk loci.
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    Serum microRNA-1233 is a specific biomarker for diagnosing acute pulmonary embolism
    (2016-05-05) Kessler, Thorsten; Erdmann, Jeanette; Vilne, Baiba; Bruse, Petra; Kurowski, Volkhard; Diemert, Patrick; Schunkert, Heribert; Sager, Hendrik B.
    Background: Circulating microRNAs (miRNAs) emerge as novel biomarkers in cardiovascular diseases. Diagnosing acute pulmonary embolism (PE) remains challenging due to a diverse clinical presentation and the lack of specific biomarkers. Here we evaluate serum miRNAs as potential biomarkers in acute PE. Methods: We enrolled 30 patients with acute, CT (computed tomography)-angiographically confirmed central PE and collected serum samples on the day of emergency room admission (1st day) and from 22 of these patients 9 months thereafter. For comparison, we examined serum samples from patients with acute non ST-segment elevation myocardial infarction (NSTEMI, n = 30) and healthy individuals (n = 12). Results: We randomly selected 16 out of 30 PE patients and screened sera from the acute (1st day) and chronic stages (9 months) for 754 miRNAs using microarrays and found 37 miRNAs to be differentially regulated. Across all miRNAs, miRNA-1233 displayed the highest fold change (FC) from acute to chronic stage (log2FC 11.5, p < 0.004). We validated miRNA-1233 by real-time quantitative polymerase chain reaction (RT-qPCR). In acute PE (1st day) we found elevated levels of miRNA-1233 in comparison to NSTEMI (log2FC 5.7, p < 0.0001) and healthy controls (log2FC 7.7, p < 0.0001). miRNA-1233 differentiated acute PE from NSTEMI patients and healthy individuals with 90 and 90 % sensitivity, and 100 and 92 % specificity [area under the curve (AUC) 0.95, p < 0.001 and 0.91, p < 0.001], respectively. Conclusions: This is the first report that identifies a miRNA that allows distinguishing acute PE from acute NSTEMI and healthy individuals with high specificity and sensitivity.