Urate-Lowering Therapy Inhibits Thoracic Aortic Aneurysm and Dissection Formation in Mice

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 β-aminopropionitrile diet, Marfan mice with fibrillin-1 haploinsufficiency (Fbn1 C1041G/+ ), 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 β-aminopropionitrile–treated mice, Fbn1 C1041G/+ 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.

Association of serum uric acid level with intracranial aneurysms: A Mendelian randomization study

“…Moreover, the mechanisms underlying the causality between elevated SUA and the heightened risk of IAs remain unclear. Nevertheless, studies on SUA in various cardiovascular diseases [ 22 ] and aortic aneurysms [ 9 , 10 ] suggest that SUA may induce inflammation, oxidative stress, and endothelial dysfunction in vessel walls [ 22 ]. Coincidentally, these pathophysiological mechanisms could be implicated in the development, progression, and rupture of IAs [ [23] , [24] , [25] ].…”

“…Inflammation plays a pivotal role across different stages of IAs from formation to rupture [ 23 ], and it appears that SUA may contribute to aortic aneurysm formation via inflammatory pathways. Studies by Yang L et al revealed that hyperuricemia could induce the formation of thoracic aortic aneurysms and the dissection by activating Fc gamma receptors (FcγR)-mediated extracellular regulated kinase 1/2 (ERK1/2) phosphorylation and macrophage inflammation, which could be reversed by urate-lowering therapy in mice model [ 9 ]. Meanwhile, Wang JC et al also indicated that hyperuricemia might exacerbate the development of abdominal aortic aneurysms via the urate transporter 1 (URAT1)/ERK/matrix metalloproteinase (MMP)-9 signaling pathway [ 10 ].…”

“…Multiple studies have postulated the involvement of SUA in the onset and progression of atherosclerosis and other cardiovascular diseases [ [5] , [6] , [7] , [8] ]. For example, the increase of SUA levels may also exacerbate the development of aortic aneurysms [ 9 , 10 ]. Given their similar histopathological characteristics, the impact of SUA levels on IAs initiation was uncertain.…”

Effect of serum uric acid on the risk of aortic aneurysm and dissection: A mendelian randomization analysis

“…A recent line of studies has explored how uric acid may relate to AAD. The study was conducted by Yang, Wu [ 28 ] in a mouse model of thoracic aortic aneurysm and dissection (TAAD). TAAD in mice was inhibited by the addition of the uric acid-lowering drug allopurinol to drinking water.…”

“…The causal relationship between uric acid and AA, as concluded in the study, suggests that uric acid may play a role in the development or progression of AA. In addition to the high uric acid mentioned in Yang, Wu [ 28 ] triggering macrophage ERK1/2 phosphorylation to promote inflammation and the development of AA through FcgR, Wang, Tsai [ 33 ]analyzed data from 107 AA patients and found that patients with serum uric acid levels higher than 9 mg/dl had a higher AA growth rate compared to those with serum uric acid levels between 4 and 7.9 mg/dl. The study revealed that uric acid mediates AA development through activation of URAT1/ERK1/2/ROS/MMP-9.…”