ETA2022 Oral Presentations Oral Session 1: Topic Highlights (6 abstracts)
Selenoprotein deficiency disorder predisposes to aortic aneurysm formation
Erik Schoenmakers 1 , Federica Marelli 2 , Helle Jørgensen 3 , W. Edward Visser 4 , Carla Moran 5 , Stefan Groeneweg 6 , Carolina Avalos 7 , Nichola Figg 3 , Alison Finigan 3 , Neha Wali 8 , Maura Agostini 9 , Hannah Wardle-Jones 8 , Greta Lyons 10 , Rosemary Rusk 11 , Deepa Gopalan 12 , Jacob Johannes Visser 13 , Martin Goddard 14 , Samer Nashef 15 , Robin Heijmen 16 , Paul Clift 17 , Sanjay Sinha 18 , Elisabeth Busch-Nentwich 19 , Ramiro Ramirez-Solis 8 , Luca Persani 20 , Martin Bennett 3 & Krishna Chatterjee 21
1Institute of Metabolic Science, Clinical Biochemistry, Cambridge, United Kingdom; 2Irccs Istituto Auxologico Italiano, Lab. of Endocrine and Metabolic Research, Lab of Endocrine and Metabolic Research, Cusano Milanino, Italy; 3University of Cambridge, Division of Cardiovascular Medicine, Cambridge, United Kingdom; 4Erasmus Medical Center, Academic Center for Thyroid Diseases, Department of Internal Medicine, Academic Center for Thyroid Diseases, Rotterdam, Netherlands; 5Endocrine Dept, Endocrine, Ucd School of Medicine, Dublin, Ireland; 6Academic Center for Thyroid Diseases, Academic Center for Thyroid Disease, Department of Internal Medicine, Erasmus Medical Center Rotterdam, The Netherlands, Department of Internal Medicine, Rotterdam, Netherlands; 7Clinica Alemana de Santiago, Department of Paediatric Endocrinology, Chile; 8Wellcome Sanger Institute, Cambridge, United Kingdom; 9Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom; 10Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, United Kingdom; 11Addenbrooke’s Hospital, Department of Cardiology, Cambridge, United Kingdom; 12Hammersmith Hospital, United Kingdom; 13Erasmus University Medical Center, Department of Radiology, Rotterdam, Netherlands; 14Royal Papworth Hospital, Department of Pathology, Cambridge, United Kingdom; 15Royal Papworth Hospital, Department of Cardiothoracic Surgery, Cambridge, United Kingdom; 16St Antonius Hospital, Department of Cardiothoracic Surgery, Nieuwegein, Netherlands; 17University Hospital Birmingham Foundation, ., Cardiology, Birmingham, United Kingdom; 18University of Cambridge, United Kingdom; 19Queen Mary University of London, School of Biological and Behavioural Sciences, London, United Kingdom; 20University of Milan, Irccs Istituto Auxologico Italiano, Ospedale San Luca, Milan, Italy; 21University of Cambridge, Wellcome-Mrc Institute of Metabolic Science, Cambridge, United Kingdom
Objectives: Mutations in SECISBP2 cause deficiency of selenoproteins, resulting in a multisystem disorder with abnormal circulating thyroid hormone and selenium levels and features due to lack of specific selenoproteins or loss of antioxidant selenoenzymes. Having observed early-onset, aneurysmal thoracic aortic dilatation in four patients with this disorder, we studied zebrafish and murine Secisbp2 mutant models to determine whether the aortic phenotype and selenoprotein deficiency are causally related.
Methods: Analyses of histology, selenoprotein deficiencies, oxidative stress, DNA damage and apoptosis in aortae and aortic vascular smooth muscle cells (VSMCs) from two patients following surgery, and in aortae from zebrafish Secisbp2 mutant and morpholino knockdown or VSMC-targeted, Secisbp2-deficient mouse models, were undertaken.
Results: Progressive, early-onset (age 10 to 41yrs) aneurysmal ascending aortic dilatation occurred in four patients with biallelic mutations in SECISBP2, but without defects in known, thoracic aortopathy, genes. Histology of aneurysmal aortae showed cystic medial necrosis, with deficiency of antioxidant selenoenzymes, oxidative membrane lipid and DNA damage and apoptosis in both medial wall of aorta and cultured, medial VSMCs. Ventral aortic dilatation increased tissue H202 content, lipid peroxidation and DNA damage were observed in adult, Secisbp2Q333X/Q333X mutant and embryonic Secisbp2 morpholino-knockdown zebrafish, with coexpression of Secisbp2 mRNA in the morpholino model rescuing these abnormalities. Tamoxifen treatment of Myh11-CreERt2/ Secisbp2flox/flox mice, conditionally abolished Secisbp2 and selenoprotein expression in the medial layer of murine aortae. Infusion of angiotensin II, an established model of thoracic aortic aneurysm (TAA) formation, caused markedly diminished survival (60%) of homozygous mice compared to wild-type or heterozygous littermates (90%), due to development of TAAs with aortic cystic medial necrosis. Loss of antioxidant selenoenzymes, oxidative stress, DNA damage and apoptosis, were features common to aortae from patients, zebrafish and mouse models of SECISBP2 deficiency. Reversal of oxidative damage and apoptosis by exposure of human aortic VSMCs to antioxidants, implicates excess ROS in their pathogenesis.
Conclusions: We have documented thoracic aortic aneurysm formation in patients with SECISBP2 mutations and similar aortopathy in zebrafish or mice with global or VSMC-targeted inactivation of Secisbp2. We suggest that SECISBP2 is a novel genetic aetiology of TAA, with oxidative stress and cell death secondary to deficiency of antioxidant selenoenzymes mediating aortic degeneration.
Article tools
My recent searches
My recently viewed abstracts
Authors
Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
© Bioscientifica 2024 |
Privacy policy |
Cookie settings
BiosciAbstracts
Bioscientifica Abstracts is the gateway to a series of products that provide a permanent, citable record of abstracts for biomedical and life science conferences.
Find out more