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Inhibition of HIPK2 Alleviates Thoracic Aortic Disease in Mice With Progressively Severe Marfan Syndrome

Authors :
Francesco Ramirez
Alan D. Weinberg
Sae-Il Murtada
Cristina I. Caescu
Jay D. Humphrey
Catherine Boileau
James M. Gallo
Bart Spronck
Pauline Arnaud
Guillaume Jondeau
John Cijiang He
Takeshi Hashimoto
Roshan Borkar
Jens Hansen
Ravi Iyengar
Wenzhen Xiao
Brittany Crockett
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.

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