Tumor necrosis factor-α decreases sarcoplasmic reticulum Ca2+-ATPase expressions via the promoter methylation in cardiomyocytes

Yu Hsun Kao, Yao Chang Chen, Chen Chuan Cheng, Ting I. Lee, Yi Jen Chen, Shih Ann Chen

研究成果: 雜誌貢獻文章

65 引文 斯高帕斯(Scopus)

摘要

OBJECTIVES: Sarcoplasmic reticulum Ca-ATPases (SERCA2a) plays an essential role in the Ca homeostasis and cardiac functions. Tumor necrosis factor-α (TNF-α) decreases the SERCA2a, which may underlie cardiac dysfunction during sepsis and heart failure. Because the promoter region of SERCA2a contains CpG islands, gene methylation should be critical in regulating SERCA2a. The present study was to evaluate whether TNF-α can modulate SERCA2a via enhancing methylation and to investigate the underlying mechanisms. DESIGN: Controlled laboratory experiment. SETTING: University research laboratory. SUBJECTS: HL-1 cardiomyocytes. INTERVENTIONS: TNF-α (1-50 ng/mL) was administered in HL-1 cardiomyocytes with and without co-administration of an NF-κB inhibitor (SN-50, 50 μg/mL), antioxidant agents (ascorbic acid, 100 μM, or coenzyme Q10, 10 μM), or methylation inhibitor (5-aza-2′-deoxycytidine, 0.1, 1 μM). MEASUREMENTS AND MAIN RESULTS: TNF-α (50 ng/mL) decreased the SERCA2a RNA and protein by quantitative polymerase chain reaction and immunoblot. Furthermore, TNF-α (50 ng/mL) increased the methylation in the SERCA2a promoter region, which was not influenced by the co-administration of SN-50, ascorbic acid, or coenzyme Q10, but was attenuated by 5-aza-2′-deoxycytidine (0.1 μM). Additionally, TNF-α (50 ng/mL) increased the expression of DNA methyltransferase 1. CONCLUSIONS: TNF-α increased DNA methyltransferase levels, thus enhancing the methylation in the SERCA2a promoter region with a result of reducing SERCA2a. These findings suggest that inhibition of hypermethylation may be a novel treatment strategy for cardiac dysfunction.
原文英語
頁(從 - 到)217-222
頁數6
期刊Critical Care Medicine
38
發行號1
DOIs
出版狀態已發佈 - 一月 2010

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

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