Parallel murine and human aortic wall genomics reveals metabolic reprogramming as key driver of abdominal aortic aneurysm progression

Autor: Lesca M. Holdt, Lars Maegdefessel, Stefan Ludwig, Albert Busch, Adrian Mahlmann, Dick Wågsäter, Jonathan Golledge, Jan H.N. Lindeman, Bernd H. Northoff, Daniel Teupser, Amanda Balboa, Gabor Gäbel, Anders Wanhainen, Vivian de Waard, Mediha Becirovic-Agic, Marcelo Heron Petri
Přispěvatelé: Medical Biochemistry, ACS - Atherosclerosis & ischemic syndromes, ACS - Heart failure & arrhythmias
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Translational Studies
Swine
Disease
elastase model
Mice
Fibrosis
Angiotensin II model
Gene expression
Clinical Studies
metabolic reprogramming
Glycolysis
Cardiac and Cardiovascular Systems
Aorta
Abdominal
Pancreatic elastase
Original Research
Kardiologi
Cardiovascular Surgery
Pancreatic Elastase
Angiotensin II
Metabolic reprogramming
Genomics
glycolysis
Abdominal aortic aneurysm
cardiovascular system
Cardiology and Cardiovascular Medicine
Human
angiotensin II model
Pathophysiology
Immune system
Aneurysm
abdominal aortic aneurysm
Vascular Biology
medicine
Diseases of the circulatory (Cardiovascular) system
Animals
Humans
human
business.industry
Kirurgi
Elastase model
medicine.disease
Mice
Inbred C57BL
Disease Models
Animal
Metabolism
RC666-701
Cancer research
gene expression
Surgery
business
Aortic Aneurysm
Abdominal
Zdroj: Journal of the American Heart Association, 10(17):e020231. Wiley-Blackwell
Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, Vol 10, Iss 17 (2021)
Journal of the American Heart Association Cardiovascular and Cerebrovascular Disease, 10(17). WILEY
ISSN: 2047-9980
Popis: 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.
Databáze: OpenAIRE
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