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Inhibition of HIPK2 Alleviates Thoracic Aortic Disease in Mice With Progressively Severe Marfan Syndrome
- Source :
- Arteriosclerosis, Thrombosis, and Vascular Biology, Arterioscler Thromb Vasc Biol
- Publication Year :
- 2021
-
Abstract
- Objective: Despite considerable research, the goal of finding nonsurgical remedies against thoracic aortic aneurysm and acute aortic dissection remains elusive. We sought to identify a novel aortic PK (protein kinase) that can be pharmacologically targeted to mitigate aneurysmal disease in a well-established mouse model of early-onset progressively severe Marfan syndrome (MFS). Approach and Results: Computational analyses of transcriptomic data derived from the ascending aorta of MFS mice predicted a probable association between thoracic aortic aneurysm and acute aortic dissection development and the multifunctional, stress-activated HIPK2 (homeodomain-interacting protein kinase 2). Consistent with this prediction, Hipk2 gene inactivation significantly extended the survival of MFS mice by slowing aneurysm growth and delaying transmural rupture. HIPK2 also ranked among the top predicted PKs in computational analyses of DEGs (differentially expressed genes) in the dilated aorta of 3 MFS patients, which strengthened the clinical relevance of the experimental finding. Additional in silico analyses of the human and mouse data sets identified the TGF (transforming growth factor)-β/Smad3 signaling pathway as a potential target of HIPK2 in the MFS aorta. Chronic treatment of MFS mice with an allosteric inhibitor of HIPK2-mediated stimulation of Smad3 signaling validated this prediction by mitigating thoracic aortic aneurysm and acute aortic dissection pathology and partially improving aortic material stiffness. Conclusions: HIPK2 is a previously unrecognized determinant of aneurysmal disease and an attractive new target for antithoracic aortic aneurysm and acute aortic dissection multidrug therapy.
- Subjects :
- Adult
Male
0301 basic medicine
Marfan syndrome
medicine.medical_specialty
Mice, 129 Strain
Fibrillin-1
Aorta, Thoracic
Dissection (medical)
Protein Serine-Threonine Kinases
Vascular Remodeling
030204 cardiovascular system & hematology
Severity of Illness Index
Thoracic aortic aneurysm
Article
Marfan Syndrome
03 medical and health sciences
Aortic aneurysm
0302 clinical medicine
Aneurysm
Internal medicine
medicine.artery
Ascending aorta
medicine
Animals
Humans
Smad3 Protein
Protein Kinase Inhibitors
Mice, Knockout
Aortic dissection
Aorta
Aortic Aneurysm, Thoracic
business.industry
medicine.disease
Mice, Inbred C57BL
Aortic Dissection
Disease Models, Animal
030104 developmental biology
Disease Progression
cardiovascular system
Cardiology
Carrier Proteins
Cardiology and Cardiovascular Medicine
business
Dilatation, Pathologic
Signal Transduction
Subjects
Details
- ISSN :
- 10795642
- Database :
- OpenAIRE
- Journal :
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Accession number :
- edsair.doi.dedup.....6074355c9715146535536d405ce7a909
- Full Text :
- https://doi.org/10.1161/atvbaha.121.316464