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

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)217-222
Number of pages6
JournalCritical Care Medicine
Volume38
Issue number1
DOIs
Publication statusPublished - Jan 2010

Fingerprint

Calcium-Transporting ATPases
Sarcoplasmic Reticulum
Cardiac Myocytes
Methylation
Tumor Necrosis Factor-alpha
coenzyme Q10
decitabine
Genetic Promoter Regions
Methyltransferases
Ascorbic Acid
CpG Islands
DNA
Adenosine Triphosphatases
Sepsis
Homeostasis
Heart Failure
Antioxidants
RNA
Polymerase Chain Reaction
Research

Keywords

  • Cardiomyocyte
  • Heart failure
  • Inflammation
  • Methylation
  • Sarcoplasmic reticulum Ca -ATPases
  • Tumor necrosis factor-α

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Tumor necrosis factor-α decreases sarcoplasmic reticulum Ca2+-ATPase expressions via the promoter methylation in cardiomyocytes. / Kao, Yu Hsun; Chen, Yao Chang; Cheng, Chen Chuan; Lee, Ting I.; Chen, Yi Jen; Chen, Shih Ann.

In: Critical Care Medicine, Vol. 38, No. 1, 01.2010, p. 217-222.

Research output: Contribution to journalArticle

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abstract = "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.",
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T1 - Tumor necrosis factor-α decreases sarcoplasmic reticulum Ca2+-ATPase expressions via the promoter methylation in cardiomyocytes

AU - Kao, Yu Hsun

AU - Chen, Yao Chang

AU - Cheng, Chen Chuan

AU - Lee, Ting I.

AU - Chen, Yi Jen

AU - Chen, Shih Ann

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N2 - 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.

AB - 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.

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KW - Heart failure

KW - Inflammation

KW - Methylation

KW - Sarcoplasmic reticulum Ca -ATPases

KW - Tumor necrosis factor-α

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