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

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

doi:10.1016/j.lfs.2020.118290

Cited by 16 publications

(13 citation statements)

References 24 publications

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“…These protective effects of allopurinol were highly associated with reductions in ROS formation and atrial fibrosis-related factors and abnormal calcium homeostasis (45). Allopurinol can improve atrial electrical remodeling by inhibiting CaMKII activity and protein expression of Na+/Ca2+ exchanger in diabetic rats (46). In aggregate, these findings indicate that oxidative stress is involved in atrial electrical remodeling caused by hyperuricemia, and XO inhibition can reduce oxidative stress and ameliorate atrial electrical remodeling.…”

Section: The Role Of Oxidative Stress On the Progress Of Elevated Ua-mentioning

confidence: 98%

The Key Role of Uric Acid in Oxidative Stress, Inflammation, Fibrosis, Apoptosis, and Immunity in the Pathogenesis of Atrial Fibrillation

Deng

Liu

Yang

et al. 2021

Front. Cardiovasc. Med.

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Atrial fibrillation (AF) is a highly prevalent cardiac arrhythmia that leads to numerous adverse outcomes including stroke, heart failure, and death. Hyperuricemia is an important risk factor that contributes to atrium injury and AF, but the underlying molecular mechanism remains to be elucidated. In this review, we discussed the scientific evidence for clarifying the role of hyperuricemia in the pathogenesis of AF. Experimental and Clinical evidence endorse hyperuricemia as an independent risk factor for the incidence of AF. Various in vivo and in vitro investigations showed that hyperuricemia might play a critical role in the pathogenesis of AF at different UA concentrations through the activation of oxidative stress, inflammation, fibrosis, apoptosis, and immunity.

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Section: The Role Of Oxidative Stress On the Progress Of Elevated Ua-mentioning

confidence: 98%

The Key Role of Uric Acid in Oxidative Stress, Inflammation, Fibrosis, Apoptosis, and Immunity in the Pathogenesis of Atrial Fibrillation

Deng

Liu

Yang

et al. 2021

Front. Cardiovasc. Med.

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“…Data were analyzed using SPSS 24.0 or Graph-Pad Prism 7.0 statistical software, and presented as mean ± standard error of mean (SEM) or percentage of at least five independent experiments (21). Fischer's exact test was used for AF susceptibility comparisons between multiple groups.…”

Section: Discussionmentioning

confidence: 99%

“…The cells were plated and subcultured until the 3 rd -4 th passages and then grouped as follows: (I) Control group: the HL-1 cells were cultured with a basic culture media and 0.1% dimethylsulfoxide (DMSO) without any other treatment. (II) Ang II group: the HL-1 cells were cultured with a basic culture media, 0.1% DMSO, and 1 μM Ang II (21) with deionized water solution for 24 h. (III) Ang II + Moricizine group: the HL-1 cells were cultured with basic culture media, 1 μM Ang II, and 30 μM moricizine with DMSO solution (modified to a final concentration of 0.1%) for 24 h. (IV) ATX II group: the HL-1 cells were cultured with a basic culture media, 0.1% DMSO, and 3nM ATX II with deionized water solution for 24 h. (V) ATX II + Moricizine group: the HL-1 cells were cultured with a basic culture media, 3nM ATX II, and 30 μM moricizine with DMSO solution (modified to a final concentration of 0.1%) for 24 h.…”

Section: Cell Culture and Groupingmentioning

confidence: 99%

Moricizine prevents atrial fibrillation by late sodium current inhibition in atrial myocytes

Tian¹,

Chen²,

Chen³

et al. 2022

J Thorac Dis

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Background: Enhanced late sodium current (INaL) is reportedly related to an increased risk of atrial fibrillation (AF). Moricizine, as a widely used anti-arrhythmia drug for suppressing ventricular tachycardia, has also been shown to prevent paroxysmal AF. However, the mechanism of its therapeutic effect remains poorly understood.Methods: Angiotensin II (Ang II) was induced in C57Bl/6 mice (male wild-type) for 4 weeks to increase the susceptibility of AF, and acetylcholine-calcium chloride was used to induce AF. The whole-cell patch-clamp technique was used to detect INaL from isolated atrial myocytes. The expression of proteins in atrial of mice and HL-1 cells were examined by Western-blot. Results:The results showed that moricizine significantly inhibited Ang II-mediated atrial enlargement and reduced AF vulnerability. We found that the densities of INaL were enhanced in Ang II-treated left and right atrial cardiomyocytes. Simultaneously, the Ang II-induced increase in INaL currents density was alleviated by the administration of moricizine, and no alteration in Nav1.5 expression was observed. In normal isolated atrial myocytes, moricizine significantly reduced Sea anemone toxin II (ATX II)-enhanced INaL density with a reduction of peak sodium currents. In addition, moricizine reduced the Ang II-induced upregulation of phosphorylated calcium/calmodulin-dependent protein kinase-II (p-CaMKII) in both the left and right atria.In HL-1 cells, moricizine also reduced the upregulation of p-CaMKII with Ang II and ATX II intervention, respectively. Conclusions: Our results indicate that Ang II enhances the INaL via activation of CaMKII. Moricizine inhibits INaL and reduces CaMKII activation, which may be one of the mechanisms of moricizine suppression of AF.

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“…Inhibition of CaMKII was able to prevent an NCX mediated I ti in isolated rabbit ventricular myocytes, which may help prevent Ca 2+ overload induced arrhythmia ( Wu et al, 1999a ). In an STZ-induced DM rat model, NCX protein expression is increased in atrial tissue, which was ameliorated by antioxidant treatment ( Yang et al, 2020 ). This antioxidant treatment also alleviated the raised levels of phosphorylated CaMKII seen in this diabetic model.…”

Section: Arrhythmogenic Targets Of Calcium/calmodulin (Ca2+/cam) Dependent Protein Kinase IImentioning

confidence: 99%

CaMKII Inhibition is a Novel Therapeutic Strategy to Prevent Diabetic Cardiomyopathy

2021

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Increasing prevalence of diabetes mellitus worldwide has pushed the complex disease state to the foreground of biomedical research, especially concerning its multifaceted impacts on the cardiovascular system. Current therapies for diabetic cardiomyopathy have had a positive impact, but with diabetic patients still suffering from a significantly greater burden of cardiac pathology compared to the general population, the need for novel therapeutic approaches is great. A new therapeutic target, calcium/calmodulin-dependent kinase II (CaMKII), has emerged as a potential treatment option for preventing cardiac dysfunction in the setting of diabetes. Within the last 10 years, new evidence has emerged describing the pathophysiological consequences of CaMKII activation in the diabetic heart, the mechanisms that underlie persistent CaMKII activation, and the protective effects of CaMKII inhibition to prevent diabetic cardiomyopathy. This review will examine recent evidence tying cardiac dysfunction in diabetes to CaMKII activation. It will then discuss the current understanding of the mechanisms by which CaMKII activity is enhanced during diabetes. Finally, it will examine the benefits of CaMKII inhibition to treat diabetic cardiomyopathy, including contractile dysfunction, heart failure with preserved ejection fraction, and arrhythmogenesis. We intend this review to serve as a critical examination of CaMKII inhibition as a therapeutic strategy, including potential drawbacks of this approach.

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

Cited by 16 publications

References 24 publications

The Key Role of Uric Acid in Oxidative Stress, Inflammation, Fibrosis, Apoptosis, and Immunity in the Pathogenesis of Atrial Fibrillation

The Key Role of Uric Acid in Oxidative Stress, Inflammation, Fibrosis, Apoptosis, and Immunity in the Pathogenesis of Atrial Fibrillation

Moricizine prevents atrial fibrillation by late sodium current inhibition in atrial myocytes

CaMKII Inhibition is a Novel Therapeutic Strategy to Prevent Diabetic Cardiomyopathy

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