Xanthine oxidase inhibitor allopurinol improves atrial electrical remodeling in diabetic rats by inhibiting CaMKII/NCX signaling

Yajuan Yang, Jinli He, Ming Yuan, Gary Tse, Kai Zhang, Zuowang Ma, Jian Li, Yue Zhang, Yunlai Gao, Yu Zhang, Ruxing Wang, Guangping Li, Tong Liu

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

Abstract

Aims: Atrial fibrillation (AF) is a common arrhythmia which is associated with higher risk of stroke, heart failure and all-cause mortality. Abnormal Ca2+ handling in diabetes mellitus (DM) can cause delayed depolarization involved with increased NCX activity. Complicated mechanisms are involved in atrial remodeling, of which CaMKII may be a key node signal. Therefore, we intend to explore whether CaMKII activation induces atrial electrical remodeling by regulating NCX expression in this study. Main methods: Adult male SD rats were used to establish a diabetic rat model, divided into three groups: the control group, DM group and allopurinol group. Hemodynamic and ECG indicators were recorded, after which electrophysiological studies were conducted. The protein expression of CaMKII, p-CaMKII, XO, MnSOD and NCX was measured by Western blot and immunohistochemistry. H&E and Masson staining were applied for observing myocardial fibrosis. HL-1 cells were cultured for the measurement of ROS generation. Key findings: The arrangement of atrial myocytes was disordered and the collagen volume fraction of the atrium tissue was elevated in the DM group compared with the control group, and improved by allopurinol. Higher incidence of inducible AF, reduced conduction velocity and higher conduction inhomogeneity were observed in diabetic rats. These electrophysiological abnormalities were accompanied by higher oxidative stress and protein expression of p-CaMKII and NCX. Allopurinol prevented the development of these abnormal changes. Significance: Allopurinol can improve atrial electrical remodeling by inhibiting CaMKII activity and protein expression of NCX. These data indicate xanthine oxidase inhibition can reduce oxidative stress and ameliorate atrial electrical remodeling.

Original languageEnglish
Article number118290
JournalLife Sciences
Volume259
DOIs
Publication statusPublished - 15 Oct 2020
Externally publishedYes

Keywords

  • Atrial fibrillation
  • Ca handling
  • Calmodulin/Ca-dependent protein kinase II
  • Na-Ca exchanger
  • Oxidative stress

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