Xanthine oxidase inhibitor febuxostat reduces atrial fibrillation susceptibility by inhibition of oxidized CaMKII in Dahl salt-sensitive rats

Abstract Oxidative stress could be a possible mechanism and a therapeutic target of atrial fibrillation (AF). However, the effects of the xanthine oxidase (XO) inhibition for AF remain to be fully elucidated. We investigated the effects of a novel XO inhibitor febuxostat on AF compared to allopurinol in hypertension rat model. Five-week-old Dahl salt-sensitive rats were fed to either low-salt (LS) (0.3% NaCl) or high-salt (HS) (8% NaCl) diet. After 4 weeks of diet, HS diet rats were divided into 3 groups: orally administered to vehicle (HS-C), febuxostat (5mg/kg/day) (HS-F), or allopurinol (50mg/kg/day) (HS-A). After 4 weeks of treatment, systolic blood pressure was significantly higher in HS-C than LS, and it was slightly but significantly decreased by treatment with each XO inhibitor. AF duration was significantly prolonged in HS-C compared with LS, and significantly suppressed in both HS-F and HS-A (LS; 5.8±3.5 sec, HS-C; 33.9±23.7 sec, HS-F; 15.0±14.1 sec, HS-A; 20.1±11.9 sec: P<0.05). Ca2+ spark frequency was obviously increased in HS-C rats and reduced in the XO inhibitor-treated rats, especially in HS-F group. Western blotting revealed that the atrial expression levels of methionine 281/282-oxidized Ca2+/Calmodulin-dependent kinase II and serine 2814-phosphorylated ryanodine receptor 2 were significantly increased in HS-C, and those were suppressed in HS-F and HS-A. Decreased expression of gap junction protein connexin 40 in HS-C was partially restored by treatment with each XO inhibitor. In conclusion, XO inhibitor febuxostat, as well as allopurinol, could reduce hypertension-related increase in AF perpetuation by restoring Ca2+ handling and gap junction.

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XANTHINE OXIDASE INHIBITOR ALLOPURINOL PREVENTS OXIDATIVE STRESS-MEDIATED ATRIAL REMODELING IN ALLOXAN-INDUCED DIABETES RABBITS

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(18)32659-7 ◽

2018 ◽

Vol 71 (11) ◽

pp. A2118

Author(s):

Yajuan Yang ◽

Jianping Zhao ◽

Jiuchun Qiu ◽

Jian Li ◽

Xue Liang ◽

...

Keyword(s):

Oxidative Stress ◽

Xanthine Oxidase ◽

Oxidase Inhibitor ◽

Atrial Remodeling ◽

Xanthine Oxidase Inhibitor

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Effects of Melatonin on Proliferation, Oxidative Stress and Cx32 Gap Junction Protein Expression in Primary Cultures of Adult Rat Hepatocytes.

Cell Structure and Function ◽

10.1247/csf.22.347 ◽

1997 ◽

Vol 22 (3) ◽

pp. 347-356 ◽

Cited By ~ 26

Author(s):

Takashi Kojima ◽

Chihiro Mochizuki ◽

Toshihiro Mitaka ◽

Yohichi Mochizuki

Keyword(s):

Oxidative Stress ◽

Protein Expression ◽

Gap Junction ◽

Primary Cultures ◽

Rat Hepatocytes ◽

Adult Rat ◽

Junction Protein ◽

Adult Rat Hepatocytes ◽

Gap Junction Protein

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The risk of atrial fibrillation associated with hyperuricemia

Ukrainian Therapeutical Journal ◽

10.30978/utj2021-1-78 ◽

2021 ◽

Author(s):

V. A. Chernyshov

Keyword(s):

Oxidative Stress ◽

Atrial Fibrillation ◽

Elevated Serum ◽

Renin Angiotensin System ◽

Oxidase Inhibitor ◽

Important Place ◽

Xanthine Oxidase Inhibitor ◽

Increased Risk ◽

The Relationship

The article summarizes mechanisms, linking hyperuricemia, the elevated serum levels of uric acid (UA), and atrial fibrillation (AF), the most frequent cardiac arrhythmia. The actuality of the problem is explained by the fact that UA is considered as an independent risk marker of AF closely associated with the onset and subsequent persistence of AF as well as by the AF increased risk in males and females with hyperuricemia. It has been shown how hyperuricemia, combined with other AF risk factors, contributeы to the development of arrhythmia, as well as the role of hyperuricemia, oxidative stress and renin‑angiotensin system (RAS) activation in the AF pathogenesis. The consideration have been given to the hyperuricemia association with a prevalence of AF among the patients with carbohydrate exchange disorders such as metabolic syndrome and type 2 diabetes mellitus as well as to the relationship between hyperuricemia and endothelial vascular dysfunction, oxidative stress, high blood concentration of systemic inflammatory markers and insulin resistance (IR). Some mechanisms of hyperuricemia participation in cardiac remodeling as a risk factor of AF are adduced. In particular, the relationship between hyperuricemia and left atrial (LA) size that could be mediated through systemic inflammation and IR is discussed. A significance of a direct impaired action of UA on LA cardiomyocytes resulted in their structural and ionic remodeling is shown. The role of xanthinoxidase (XO) activation in initiation of oxidative stress and inflammation in cardiomyocytes and endothelial cells is discussed. All these mechanisms are emphasized to be able to shorten a potential of action of atrial cardiomyocytes as well as to reduce a threshold of re‑entry mechanism initiation and to promote an appearance of the first and the following AF episodes. An important place in the review is taken for an intracellular UA and its cellular transporters in the context of their participation in pathogenesis of AF. The possibilities of drug hyperuricemia correction have been described in regards the reduction of AF risk, in particular, the role of reducing of the oxidative stress intensity with the use of xanthine oxidase inhibitor allopurinol, the inhibitor of NADPH oxidase apocynin, the antioxidant N‑acetylcysteine in the reduction of the risk of onset and subsequent recurrences of AF episodes, and transition of arrhythmia in the persistent form. Some perspectives of probenecid (an inhibitor of UA intracellular transporter activity) usage in the reduction of AF risk due to such of its mechanisms as a reduction of intracellular UA accumulation and antiapoptotic action as well as an ability of this agent to inhibit a locally activated oxidative stress and locally activated tissue RAS are discussed. A significance of the further detailed study of pathophysiological mechanisms of AF in hyperuricemia is emphasized for elaboration of the most effective practical recommendations in prevention of this arrhythmia in persons with UA exchange disorders.

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