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Selenoprotein deficiency disorder predisposes to aortic aneurysm formation.

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.

SUBMITTER: Schoenmakers E

PROVIDER: S-EPMC10693596 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Selenoprotein deficiency disorder predisposes to aortic aneurysm formation.

Schoenmakers Erik E Marelli Federica F Jørgensen Helle F HF Visser W Edward WE Moran Carla C Groeneweg Stefan S Avalos Carolina C Jurgens Sean J SJ Figg Nichola N Finigan Alison A Wali Neha N Agostini Maura M Wardle-Jones Hannah H Lyons Greta G Rusk Rosemary R Gopalan Deepa D Twiss Philip P Visser Jacob J JJ Goddard Martin M Nashef Samer A M SAM Heijmen Robin R Clift Paul P Sinha Sanjay S Pirruccello James P JP Ellinor Patrick T PT Busch-Nentwich Elisabeth M EM Ramirez-Solis Ramiro R Murphy Michael P MP Persani Luca L Bennett Martin M Chatterjee Krishna K

Nature communications 20231202 1

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 ...[more]

PMID: 38042913

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Project description:RationaleAbdominal aortic aneurysms (AAAs) are a chronic inflammatory vascular disease for which pharmacological treatments are not available. A mouse model of AAA formation involves chronic infusion of angiotensin II (AngII), and previous studies indicated a primary role for the AngII type 1a receptor in AAA formation. β-arrestin (βarr)-2 is a multifunctional scaffolding protein that binds G-protein-coupled receptors such as AngII type 1a and regulates numerous signaling pathways and pathophysiological processes. However, a role for βarr2 in AngII-induced AAA formation is currently unknown.ObjectiveTo determine whether βarr2 played a role in AngII-induced AAA formation in mice.Methods and resultsTreatment of βarr2(+/+) and βarr2(-/-) mice on the hyperlipidemic apolipoprotein E-deficient (apoE(-/-)) background or on normolipidemic C57BL/6 background with AngII for 28 days indicated that βarr2 deficiency significantly attenuated AAA formation. βarr2 deficiency attenuated AngII-induced expression of cyclooxygenase-2, monocyte chemoattractant protein-1, macrophage inflammatory protein 1α, and macrophage infiltration. AngII also increased the levels of phosphorylated extracellular signal-regulated kinase 1/2 in apoE(-/-)/βarr2(+/+) aortas, whereas βarr2 deficiency diminished this increase. Furthermore, inhibition of extracellular signal-regulated kinase 1/2 activation with CI1040 (100 mg/kg per day) reduced the level of AngII-induced cyclooxygenase-2 expression in apoE(-/-)/βarr2(+/+) mice to the level observed in apoE(-/-)/βarr2(-/-) mice. AngII treatment also increased matrix metalloproteinase expression and disruption of the elastic layer in apoE(-/-)/βarr2(+/+) aortas, and βarr2 deficiency reduced these effects.Conclusionsβarr2 contributes to AngII-induced AAA formation in mice by phosphorylated extracellular signal-regulated kinase 1/2-mediated cyclooxygenase-2 induction and increased inflammation. These studies suggest that for the AngII type 1a receptor, G-protein-independent, βarr2-dependent signaling plays a major role in AngII-induced AAA formation.

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Selenoprotein deficiency disorder predisposes to aortic aneurysm formation.

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Selenoprotein deficiency disorder predisposes to aortic aneurysm formation.

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