Allopurinol blocks aortic aneurysm in a mouse model of Marfan syndrome via reducing aortic oxidative stress

Rodriguez-Rovira, Isaac; Arce, Cristina; Rycke, Karo De; Pérez, Belén; Carretero, Aitor; Arbones, M.; Teixidó-Turà, Gisela; Campuzano, Victoria; Jiménez‐Altayó, Francesc; Egea, Gustavo

doi:10.1016/j.freeradbiomed.2022.11.001

Cited by 16 publications

(15 citation statements)

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“…Of interest, a recent study found the similar protective effect of allopurinol in Marfan mice as we observed, nevertheless, they found that this effect was via reducing aortic xanthine oxidoreductase activity and oxidative stress but not by altering uric acid levels. 53 The different changes in uric acid may attribute to the variation in anesthesia, blood sampling protocols, and detection methods. [54][55][56] Notably, adenine diet-induced TAAD is sex dependent.…”

Section: Discussionmentioning

confidence: 99%

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

Liu

Luo

et al. 2023

ATVB

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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.

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Section: Discussionmentioning

confidence: 99%

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

Liu

Luo

et al. 2023

ATVB

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“…Biochemical, molecular and pharmacological studies have shown that xanthine oxidoreductase (XOR) is also a relevant source of ROS in the cardiovascular system [ 13 , 14 , 15 ]. Although the participation of XOR in WBS has not been reported yet; however, other connective tissue diseases, such as Loeys-Dietz and Marfan syndromes, are associated with increased XOR protein levels in aortic samples [ 16 , 17 ]. Interestingly, ROS generated by hypoxanthine and xanthine oxidase can be inhibited by curcumin (CUR) [ 18 ] as well as verapamil hydrochloride (VER) [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

The Combined Treatment of Curcumin with Verapamil Ameliorates the Cardiovascular Pathology in a Williams–Beuren Syndrome Mouse Model

Abdalla

Ortiz‐Romero

Rodriguez-Rovira

et al. 2023

IJMS

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Williams–Beuren syndrome (WBS) is a rare disorder caused by a recurrent microdeletion with hallmarks of cardiovascular manifestations, mainly supra-valvular aortic stenosis (SVAS). Unfortunately, there is currently no efficient treatment. We investigated the effect of chronic oral treatment with curcumin and verapamil on the cardiovascular phenotype of a murine model of WBS harbouring a similar deletion, CD (complete deletion) mice. We analysed systolic blood pressure in vivo and the histopathology of the ascending aorta and the left ventricular myocardium to determine the effects of treatments and their underlying mechanism. Molecular analysis showed significantly upregulated xanthine oxidoreductase (XOR) expression in the aorta and left ventricular myocardium of CD mice. This overexpression is concomitant with increased levels of nitrated proteins as a result of byproduct-mediated oxidative stress damage, indicating that XOR-generated oxidative stress impacts the pathophysiology of cardiovascular manifestations in WBS. Only the combined therapy of curcumin and verapamil resulted in a significant improvement of cardiovascular parameters via activation of the nuclear factor erythroid 2 (NRF2) and reduction of XOR and nitrated protein levels. Our data suggested that the inhibition of XOR and oxidative stress damage could help prevent the severe cardiovascular injuries of this disorder.

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“…Biochemical, molecular and pharmacological studies further implicate xanthine oxidoreductase (XOR) as a source of ROS in the cardiovascular system (Kinugasa et al, 2003; Engberding et al, 2004; Polito et al, 2021). Although the participation of XOR in WBS is unknown, related diseases as Loeys-Dietz and Marfan syndromes showed XOR protein levels increased in aortic samples (Soto et al, 2020; Rodríguez-Rovira et al, 2022). Previous studies have reported that ROS generated by hypoxanthine and xanthine oxidase were inhibited by curcumin (Akter et al, 2020) and the calcium channel blocker verapamil hydrochloride (Liang et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Curcumin combined with verapamil improve cardiovascular phenotype of a Williams-Beuren Syndrome mice model reducing oxidative stress

Abdalla

Ortiz‐Romero

Rodriguez-Rovira

et al. 2022

Preprint

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Williams-Beuren syndrome (WBS) is a rare neurodevelopmental disorder with hallmarks in the cardiovascular manifestations and no well-defined therapeutic strategies. We investigated the progression of cardiovascular phenotype present in CD (complete deletion) mice, a murine model of WBS, after chronic treatment with curcumin and verapamil, both compounds with positive effects on related pathologies. Treatment was administered orally dissolved in drinking water. After measuring in-vivo systolic blood pressure, aortic and left ventricular myocardium were histological and molecular analysed to determine the effects of treatment and its underlying mechanism in CD mice. We observed upregulated xanthine oxidoreductase (XOR) expression in both aortic and left ventricular myocardium of CD mice. This overexpression is concomitant with increased levels of nitrated proteins as example of byproduct-mediated oxidative stress damage, indicating of XOR-generated oxidative stress impact on the pathophysiology of cardiovascular manifestations in WBS, and suggesting that the inhibition of XOR and/or oxidative stress damage could help to ameliorate the severe cardiovascular injuries presented in WBS.

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Allopurinol blocks aortic aneurysm in a mouse model of Marfan syndrome via reducing aortic oxidative stress

Cited by 16 publications

References 91 publications

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

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

The Combined Treatment of Curcumin with Verapamil Ameliorates the Cardiovascular Pathology in a Williams–Beuren Syndrome Mouse Model

Curcumin combined with verapamil improve cardiovascular phenotype of a Williams-Beuren Syndrome mice model reducing oxidative stress

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