Urate-Lowering Therapy Inhibits Thoracic Aortic Aneurysm and Dissection Formation in Mice.
Arterioscler Thromb Vasc Biol
; 43(6): e172-e189, 2023 06.
Article
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| MEDLINE
| ID: mdl-37128913
ABSTRACT
BACKGROUND:
Thoracic aortic aneurysm and dissection (TAAD) is a highly lethal vascular disease without effective drug therapy. Whether elevated serum concentrations of uric acid are involved in TAAD development remains unclear.METHODS:
Serum uric acid levels were detected in different TAAD mouse models and patients. The urate-lowering drug allopurinol was administered in the drinking water of TAAD mice. Adenine diet-induced mice were established to investigate the role of hyperuricemia in TAAD formation and RNA-sequencing of thoracic aortas from these mice was performed.RESULTS:
We found serum uric acid levels were elevated in various mouse TAAD models, including mice fed a ß-aminopropionitrile diet, Marfan mice with fibrillin-1 haploinsufficiency (Fbn1C1041G/+), and ApoE-/- mice infused with Ang II (angiotensin II), as well as in patients with TAAD. Administration of urate-lowering drug allopurinol in the drinking water significantly alleviated TAAD formation in ß-aminopropionitrile-treated mice, Fbn1C1041G/+ mice, and Ang II-infused ApoE-/- mice. Moreover, an adenine diet was used to induce hyperuricemia in mice. Intriguingly, a 4-week adenine diet feeding directly induced TAAD formation characterized by increased maximal thoracic aortic diameters and severe elastin degradation, which were ameliorated by allopurinol. Unbiased RNA-sequencing in mouse thoracic aortas suggested that FcγR (Fc gamma receptor) was upregulated upon adenine diet, but reciprocally repressed by allopurinol. Mechanistically, hyperuricemia activated FcγR-mediated ERK1/2 (extracellular signal-regulated kinase 1/2) phosphorylation to induce macrophage inflammation and TAAD development, which was abrogated by allopurinol or FcγR deficiency.CONCLUSIONS:
This study uncovered an important and previously unrecognized role of hyperuricemia in mediating the pathogenesis of TAAD, and uric acid-lowering drug may represent a promising therapeutic approach for TAAD.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Agua Potable
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Aneurisma de la Aorta Torácica
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Hiperuricemia
/
Disección Aórtica
Límite:
Animals
Idioma:
En
Revista:
Arterioscler Thromb Vasc Biol
Asunto de la revista:
ANGIOLOGIA
Año:
2023
Tipo del documento:
Article