: Aortic aneurysms, which may dissect or rupture acutely and be lethal, can be a part of multisystem disorders that have a heritable basis. We report four patients with deficiency of selenocysteine-containing proteins due to selenocysteine Insertion Sequence Binding Protein 2 (SECISBP2) mutations who show early-onset, progressive, aneurysmal dilatation of the ascending aorta due to cystic medial necrosis. Zebrafish and male mice with global or vascular smooth muscle cell (VSMC)-targeted disruption of Secisbp2 respectively show similar aortopathy. Aortas from patients and animal models exhibit raised cellular reactive oxygen species, oxidative DNA damage and VSMC apoptosis. Antioxidant exposure or chelation of iron prevents oxidative damage in patient's cells and aortopathy in the zebrafish model. Our observations suggest a key role for oxidative stress and cell death, including via ferroptosis, in mediating aortic degeneration.

Selenoprotein deficiency disorder predisposes to aortic aneurysm formation / E. Schoenmakers, F. Marelli, H.F. Jørgensen, W.E. Visser, C. Moran, S. Groeneweg, C. Avalos, S.J. Jurgens, N. Figg, A. Finigan, N. Wali, M. Agostini, H. Wardle-Jones, G. Lyons, R. Rusk, D. Gopalan, P. Twiss, J.J. Visser, M. Goddard, S.A.M. Nashef, R. Heijmen, P. Clift, S. Sinha, J.P. Pirruccello, P.T. Ellinor, E.M. Busch-Nentwich, R. Ramirez-Solis, M.P. Murphy, L. Persani, M. Bennett, K. Chatterjee. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 14:1(2023 Dec 02), pp. 7994.1-7994.14. [10.1038/s41467-023-43851-6]

Selenoprotein deficiency disorder predisposes to aortic aneurysm formation

F. Marelli
Primo
Investigation
;
L. Persani
Writing – Review & Editing
;
2023

Abstract

: Aortic aneurysms, which may dissect or rupture acutely and be lethal, can be a part of multisystem disorders that have a heritable basis. We report four patients with deficiency of selenocysteine-containing proteins due to selenocysteine Insertion Sequence Binding Protein 2 (SECISBP2) mutations who show early-onset, progressive, aneurysmal dilatation of the ascending aorta due to cystic medial necrosis. Zebrafish and male mice with global or vascular smooth muscle cell (VSMC)-targeted disruption of Secisbp2 respectively show similar aortopathy. Aortas from patients and animal models exhibit raised cellular reactive oxygen species, oxidative DNA damage and VSMC apoptosis. Antioxidant exposure or chelation of iron prevents oxidative damage in patient's cells and aortopathy in the zebrafish model. Our observations suggest a key role for oxidative stress and cell death, including via ferroptosis, in mediating aortic degeneration.
Settore MED/13 - Endocrinologia
Settore MED/11 - Malattie dell'Apparato Cardiovascolare
2-dic-2023
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/1020410
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