Downregulated DKK2 may serve as a molecular mechanism of high-fat diet-induced myocardial injury via Wnt/β-catenin pathway

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences Pub Date : 2025-01-15 DOI:10.1016/j.lfs.2024.123306

Yixuan Wang , Di Chen , Ye Pu , Jiahao Shi , Congxiang Yi , Jie Chen , Guangxiang Yang , Yang Cui , Yu Nie , Liyuan Zhang , Xiaowei Wei , Qin Yu

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Abstract

Objective

High-fat diet could induce structural and functional disorders of the heart, but the underlying mechanism remains elusive. This study aimed to explore related mechanism of obesity cardiomyopathy.

Methods

Obesity model was established by feeding rats with a high-fat diet, and H9c2 cells were stimulated with palmitic acid to mimic high-fat stimulation. Whole transcriptome analysis results showed that the expression of Dickkopf-2 (DKK2) in obesity cardiomyopathy group was significantly lower than that in control group and simple obesity group. Overexpression and knockdown of DKK2 was achieved by infection with lentivirus. Weight, blood glucose, lipids, blood pressure, and insulin, HE staining, Sirius red staining and echocardiography results were analyzed in rats at 8 and 16 weeks after various interventions. qRT-PCR and western blots were used to detect the expression of RNAs and proteins.

Results

High-fat diet-induced obese rats presented with changes in serum lipid, insulin, and increases in myocardial inflammation and fibrosis. Protein and mRNA expression levels of DKK2 were significantly decreased in the obesity cardiomyopathy group compared with the obesity and control group. In vitro, knockdown of DKK2 activated β-catenin/Wnt3a pathway, while overexpress of DKK2 inhibited β-catenin/Wnt3a expression.

Conclusion

Activating DKK2 may serve as a novel therapeutic intervention option for obesity cardiomyopathy and obesity-related metabolic disorders, and future studies are needed to validate this hypothesis.

Abstract Image

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DKK2的下调可能通过Wnt/β-catenin通路参与高脂饮食诱导心肌损伤的分子机制。

目的：高脂肪饮食可引起心脏结构和功能紊乱，但其机制尚不明确。本研究旨在探讨肥胖型心肌病的相关机制。方法：采用高脂饲料喂养大鼠，建立肥胖模型，用棕榈酸刺激H9c2细胞模拟高脂刺激。全转录组分析结果显示，肥胖型心肌病组Dickkopf-2 （DKK2）的表达明显低于对照组和单纯性肥胖组。通过慢病毒感染实现DKK2的过表达和低表达。在各种干预措施后的第8周和第16周，对大鼠的体重、血糖、血脂、血压和胰岛素、HE染色、天狼星红染色和超声心动图结果进行分析。采用qRT-PCR和western blots检测rna和蛋白的表达。结果：高脂饮食诱导的肥胖大鼠出现血脂、胰岛素的改变，心肌炎症和纤维化增加。与肥胖和对照组相比，肥胖心肌病组DKK2蛋白和mRNA表达水平显著降低。在体外，DKK2的下调激活了β-catenin/Wnt3a通路，而DKK2的过表达抑制了β-catenin/Wnt3a的表达。结论：激活DKK2可能是肥胖型心肌病和肥胖相关代谢紊乱的一种新的治疗干预选择，需要进一步的研究来验证这一假设。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.