Xanthine oxidase inhibitor allopurinol prevents oxidative stress-mediated atrial remodeling in alloxan-induced diabetes mellitus rabbits

Yajuan Yang, Jianping Zhao, Jiuchun Qiu, Jian Li, Xue Liang, Zhiwei Zhang, Xiaowei Zhang, Huaying Fu, Panagiotis Korantzopoulos, Konstantinos P. Letsas, Gary Tse, Guangping Li, Tong Liu

Research output: Contribution to journalArticlepeer-review

48 Citations (Scopus)

Abstract

Background--There are several mechanisms, including inflammation, oxidative stress and abnormal calcium homeostasis, involved in the pathogenesis of atrial fibrillation. In diabetes mellitus (DM), increased oxidative stress may be attributable to higher xanthine oxidase activity. In this study, we examined the relationship between oxidative stress and atrial electrical and structural remodeling, and calcium handling abnormalities, and the potential beneficial effects of the xanthine oxidase inhibitor allopurinol upon these pathological changes. Methods and Results--Ninety rabbits were randomly and equally divided into 3 groups: control, DM, and allopurinol-treated DM group. Echocardiographic and hemodynamic assessments were performed in vivo. Serum and tissue markers of oxidative stress and atrial fibrosis, including the protein expression were examined. Atrial interstitial fibrosis was evaluated by Masson trichrome staining. ICaL was measured from isolated left atrial cardiomyocytes using voltage-clamp techniques. Confocal microscopy was used to detect intracellular calcium transients. The Ca2+ handling protein expression was analyzed by Western blotting. Mitochondrial-related proteins were analyzed as markers of mitochondrial function. Compared with the control group, rabbits with DM showed left ventricular hypertrophy, increased atrial interstitial fibrosis, oxidative stress and fibrosis markers, ICaL and intracellular calcium transient, and atrial fibrillation inducibility. These abnormalities were alleviated by allopurinol treatment. Conclusions--Allopurinol, via its antioxidant effects, reduces atrial mechanical, structural, ion channel remodeling and mitochondrial synthesis abnormalities induced by DM-related increases in oxidative stress.

Original languageEnglish
Article numbere008807
JournalJournal of the American Heart Association
Volume7
Issue number10
DOIs
Publication statusPublished - 15 May 2018
Externally publishedYes

Keywords

  • Allopurinol
  • Atrial fibrillation
  • Calcium signaling
  • Diabetes mellitus
  • Mitochondria
  • Oxidative stress
  • Xanthine oxidase

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