TY - JOUR
T1 - Selenoprotein deficiency disorder predisposes to aortic aneurysm formation
AU - Schoenmakers, Erik
AU - Marelli, Federica
AU - Jørgensen, Helle F.
AU - Visser, W. Edward
AU - Moran, Carla
AU - Groeneweg, Stefan
AU - Avalos, Carolina
AU - Jurgens, Sean J.
AU - Figg, Nichola
AU - Finigan, Alison
AU - Wali, Neha
AU - Agostini, Maura
AU - Wardle-Jones, Hannah
AU - Lyons, Greta
AU - Rusk, Rosemary
AU - Gopalan, Deepa
AU - Twiss, Philip
AU - Visser, Jacob J.
AU - Goddard, Martin
AU - Nashef, Samer A. M.
AU - Heijmen, Robin
AU - Clift, Paul
AU - Sinha, Sanjay
AU - Pirruccello, James P.
AU - Ellinor, Patrick T.
AU - Busch-Nentwich, Elisabeth M.
AU - Ramirez-Solis, Ramiro
AU - Murphy, Michael P.
AU - Persani, Luca
AU - Bennett, Martin
AU - Chatterjee, Krishna
PY - 2023/12/1
Y1 - 2023/12/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85178380449
UR - https://www.ncbi.nlm.nih.gov/pubmed/38042913
U2 - 10.1038/s41467-023-43851-6
DO - 10.1038/s41467-023-43851-6
M3 - Article
C2 - 38042913
SN - 2041-1723
VL - 14
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 7994
ER -