Parallel Murine and Human Aortic Wall Genomics Reveals Metabolic Reprogramming as Key Driver of Abdominal Aortic Aneurysm Progression

Research output: Contribution to journalResearch articleContributedpeer-review


  • Gabor Gäbel - , Helios Klinikum Krefeld (Author)
  • Bernd H Northoff - , Ludwig Maximilian University of Munich (Author)
  • Amanda Balboa - , Uppsala University (Author)
  • Mediha Becirovic-Agic - , Uppsala University (Author)
  • Marcelo Petri - , Uppsala University (Author)
  • Albert Busch - , Technical University of Munich (Author)
  • Lars Maegdefessel - , Klinikum Rechts der Isar (MRI TUM) (Author)
  • Adrian Mahlmann - , Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus Dresden (Author)
  • Stefan Ludwig - , Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus Dresden (Author)
  • Daniel Teupser - , Ludwig Maximilian University of Munich (Author)
  • Vivian de Waard - , Amsterdam University Medical Centers (UMC) (Author)
  • Jonathan Golledge - , Queensland Research Centre for Peripheral Vascular Disease College of Medicine and Dentistry James Cook University Townsville Qld. Australia (Author)
  • Anders Wanhainen - , Uppsala University (Author)
  • Dick Wågsäter - , Uppsala University (Author)
  • Lesca M Holdt - , Ludwig Maximilian University of Munich (Author)
  • Jan H N Lindeman - , Department of Vascular Surgery Leiden University Medical Center (LUMC) Leiden The Netherlands (Author)


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.


Original languageEnglish
Article numbere020231
JournalJournal of the American Heart Association
Issue number17
Publication statusPublished - 7 Sept 2021

External IDs

PubMedCentral PMC8649280
Scopus 85114795470


Sustainable Development Goals


  • Angiotensin II, Animals, Aorta, Abdominal/pathology, Aortic Aneurysm, Abdominal/chemically induced, Disease Models, Animal, Fibrosis, Genomics, Humans, Mice, Mice, Inbred C57BL, Pancreatic Elastase, Swine