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 with allopurinol in hypertension rat model. Five-week-old Dahl salt-sensitive rats were fed 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 three groups: orally administered to vehicle (HS-C), febuxostat (5 mg/kg/day) (HS-F), or allopurinol (50 mg/kg/day) (HS-A). After 4 weeks of treatment, systolic blood pressure (SBP) 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 s, HS-C; 33.9 ± 23.7 s, HS-F; 15.0 ± 14.1 s, HS-A; 20.1 ± 11.9 s: 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 Met281/282-oxidized Ca2+/Calmodulin-dependent kinase II (CaMKII) and Ser2814-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.

• Authors: DongZhu Xu, Nobuyuki Murakoshi, Kazuko Tajiri, Feng Duo, Yuta Okabe, Yoshiko Murakata, Zixun Yuan, Siqi Li, Kazuhiro Aonuma, Zonghu Song, Yuzuno Shimoda, Haruka Mori, Akira Sato, Akihiko Nogami, Kazutaka Aonuma, Masaki Ieda
• Journal: Clinical science (London, England : 1979) (Clin Sci (Lond)) Vol. 135 Issue 20 Pg. 2409-2422 (10 29 2021) ISSN: 1470-8736 [Electronic] England
• PMID: 34386810 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Author(s).

Chemical References

• Connexins
• Enzyme Inhibitors
• RyR2 protein, rat
• Ryanodine Receptor Calcium Release Channel
• Sodium Chloride, Dietary
• Febuxostat
• Allopurinol
• Xanthine Oxidase
• Calcium-Calmodulin-Dependent Protein Kinase Type 2

Topics

• Allopurinol (pharmacology)
• Animals
• Atrial Fibrillation (enzymology, genetics, physiopathology, prevention & control)
• Calcium Signaling
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (genetics, metabolism)
• Connexins (genetics, metabolism)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Febuxostat (pharmacology)
• Fibrosis
• Gap Junctions (drug effects, enzymology, pathology)
• Hypertension (drug therapy, enzymology, genetics, physiopathology)
• Male
• Myocytes, Cardiac (drug effects, enzymology, pathology)
• Oxidation-Reduction
• Phosphorylation
• Rats, Inbred Dahl
• Ryanodine Receptor Calcium Release Channel (metabolism)
• Sodium Chloride, Dietary
• Xanthine Oxidase (antagonists & inhibitors, metabolism)
• Gap Junction alpha-5 Protein
• Rats