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Parallel Murine and Human Aortic Wall Genomics Reveals Metabolic Reprogramming as Key Driver of Abdominal Aortic Aneurysm Progression
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- Gabel, Gabor (författare)
- HEUOS Klinikum Krefeld, Dept Vasc Surg, Krefeld, Germany.
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- Northoff, Bernd H. (författare)
- Ludwig Maximilians Univ Munchen, Inst Lab Med, Munich, Germany.
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- Balboa Ramilo, Amanda (författare)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- HEUOS Klinikum Krefeld, Dept Vasc Surg, Krefeld, Germany Ludwig Maximilians Univ Munchen, Inst Lab Med, Munich, Germany. (creator_code:org_t)
- John Wiley & Sons, 2021
- 2021
- Engelska.
- Ingår i: Journal of the American Heart Association. - : John Wiley & Sons. - 2047-9980 .- 2047-9980. ; 10:17
- Tidskriftsartikel (refereegranskat)
Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Kirurgi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Surgery (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Kardiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)
Nyckelord
- abdominal aortic aneurysm
- angiotensin II model
- elastase model
- gene expression
- glycolysis
- human
- metabolic reprogramming
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- art (ämneskategori)
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