Parallel Murine and Human Aortic Wall Genomics Reveals Metabolic Reprogramming as Key Driver of Abdominal Aortic Aneurysm Progression
Journal of the American Heart Association, vol. 10, pp. e020231
Abstract
Background While numerous interventions effectively interfered with abdominal aortic aneurysm (AAA) formation/progression in preclinical models, none of the successes translated into clinical success. Hence, a systematic exploration of parallel and divergent processes in clinical AAA disease and its 2 primary models (the porcine pancreatic elastase and angiotensin-II infusion [AngII] murine model) was performed to identify mechanisms relevant for aneurysm disease. Methods and Results This study combines Movat staining and pathway analysis for histological and genomic comparisons between clinical disease and its models. The impact of a notable genomic signal for metabolic reprogramming was tested in a rescue trial (AngII model) evaluating the impact of 1-(4-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one (PFK15)-mediated interference with main glycolytic switch PFKFB3. Histological evaluation characterized the AngII model as a dissection model that is accompanied by adventitial fibrosis. The porcine pancreatic elastase model showed a transient inflammatory response and aortic dilatation, followed by stabilization and fibrosis. Normalization of the genomic responses at day 14 confirmed the self-limiting nature of the porcine pancreatic elastase model. Clear parallel genomic responses with activated adaptive immune responses, and particularly strong signals for metabolic switching were observed in human AAA and the AngII model. Rescue intervention with the glycolysis inhibitor PFK15 in the AngII model showed that interference with the glycolytic switching quenches aneurysm formation. Conclusions Despite clear morphological contrasts, remarkable genomic parallels exist for clinical AAA disease and the AngII model. The metabolic response appears causatively involved in AAA progression and provides a novel therapeutic target. The clear transient genomic response classifies the porcine pancreatic elastase model as a disease initiation model.
Authors 16
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Affiliation as printed
Department of Vascular Surgery HELIOS Klinikum Krefeld Krefeld Germany
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Institut für Laboratoriumsmedizin · Ludwig-Maximilians-Universität München
Affiliation as printed
Institute of Laboratory Medicine Ludwig‐Maximilians‐University Munich Munich Germany
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Affiliation as printed
Department of Medical Cell Biology Uppsala University Uppsala Sweden
Amanda Balboa Department of Medical Cell Biology, , Uppsala University, , Uppsala, , Sweden
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Affiliation as printed
Department of Medical Cell Biology Uppsala University Uppsala Sweden
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Affiliation as printed
Department of Medical Cell Biology Uppsala University Uppsala Sweden
Marcelo Petri Department of Medical Cell Biology, , Uppsala University, , Uppsala, , Sweden
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TUM Klinikum · Technical University of Munich
Affiliation as printed
Department of Vascular and Endovascular Surgery Technical University Munich Munich Germany
Albert Busch Department of Vascular and Endovascular Surgery, , Technical University Munich, , Munich, , Germany
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TUM Klinikum · Technical University of Munich
Affiliation as printed
Department of Vascular and Endovascular Surgery Technical University Munich Munich Germany
Lars Maegdefessel https://orcid.org/0000-0001-5228-2634 Department of Vascular and Endovascular Surgery, , Technical University Munich, , Munich, , Germany
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University Hospital Carl Gustav Carus · Technische Universität Dresden
Affiliation as printed
University Centre for Vascular Medicine University Hospital Carl Gustav CarusTechnical University Dresden Dresden Germany
Adrian Mahlmann University Centre for Vascular Medicine, , University Hospital Carl Gustav Carus, Technical University Dresden, , Dresden, , Germany
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University Hospital Carl Gustav Carus · Technische Universität Dresden
Affiliation as printed
University Centre for Vascular Medicine University Hospital Carl Gustav CarusTechnical University Dresden Dresden Germany
Stefan Ludwig University Centre for Vascular Medicine, , University Hospital Carl Gustav Carus, Technical University Dresden, , Dresden, , Germany
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Institut für Laboratoriumsmedizin · Ludwig-Maximilians-Universität München
Affiliation as printed
Institute of Laboratory Medicine Ludwig‐Maximilians‐University Munich Munich Germany
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Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam
Affiliation as printed
Department Medical Biochemistry Amsterdam University Medical CentersAmsterdam Cardiovascular SciencesUniversity of Amsterdam Amsterdam The Netherlands
Vivian de Waard Department Medical Biochemistry, , Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences, University of Amsterdam, , Amsterdam, , The Netherlands
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Affiliation as printed
Queensland Research Centre for Peripheral Vascular Disease College of Medicine and Dentistry James Cook University Townsville Qld. Australia
Jonathan Golledge https://orcid.org/0000-0002-5779-8848 Queensland Research Centre for Peripheral Vascular Disease, , College of Medicine and Dentistry, , James Cook University, , Townsville, , Qld., , Australia
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Affiliation as printed
Department of Surgical Sciences Section of Vascular Surgery Uppsala University Uppsala Sweden
Anders Wanhainen Department of Surgical Sciences, , Section of Vascular Surgery, , Uppsala University, , Uppsala, , Sweden
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Affiliation as printed
Department of Medical Cell Biology Uppsala University Uppsala Sweden
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Institut für Laboratoriumsmedizin · Ludwig-Maximilians-Universität München
Affiliation as printed
Institute of Laboratory Medicine Ludwig‐Maximilians‐University Munich Munich Germany
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Jan H.N. Lindeman Aachen Department of Vascular Surgery Leiden University Medical Center (LUMC) Leiden The Netherlands
Leiden University Medical Center
Affiliation as printed
Department of Vascular Surgery Leiden University Medical Center (LUMC) Leiden The Netherlands
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