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Urate-Lowering Therapy Inhibits Thoracic Aortic Aneurysm and Dissection Formation in Mice.
- Source :
-
Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2023 Jun; Vol. 43 (6), pp. e172-e189. Date of Electronic Publication: 2023 Apr 27. - Publication Year :
- 2023
-
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.<br />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.<br />Results: We found serum uric acid levels were elevated in various mouse TAAD models, including mice fed a β-aminopropionitrile diet, Marfan mice with fibrillin-1 haploinsufficiency ( Fbn1 <superscript> C1041G/+ </superscript> ), and ApoE <superscript> -/- </superscript> 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 β-aminopropionitrile-treated mice, Fbn1 <superscript> C1041G/+ </superscript> mice, and Ang II-infused ApoE <superscript> -/- </superscript> 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.<br />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.<br />Competing Interests: Disclosures None.
- Subjects :
- Mice
Animals
Uric Acid
Aminopropionitrile adverse effects
Allopurinol adverse effects
Receptors, IgG
Signal Transduction
RNA
Mice, Inbred C57BL
Disease Models, Animal
Drinking Water adverse effects
Hyperuricemia chemically induced
Hyperuricemia drug therapy
Aortic Aneurysm, Thoracic chemically induced
Aortic Aneurysm, Thoracic genetics
Aortic Aneurysm, Thoracic prevention & control
Aortic Dissection chemically induced
Aortic Dissection genetics
Aortic Dissection prevention & control
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4636
- Volume :
- 43
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Arteriosclerosis, thrombosis, and vascular biology
- Publication Type :
- Academic Journal
- Accession number :
- 37128913
- Full Text :
- https://doi.org/10.1161/ATVBAHA.122.318788