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Tumor necrosis factor-alpha 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.
  • Kao YH; Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan.
Crit Care Med ; 38(1): 217-22, 2010 Jan.
Article en En | MEDLINE | ID: mdl-19730253
ABSTRACT

OBJECTIVES:

Sarcoplasmic reticulum Ca-ATPases (SERCA2a) plays an essential role in the Ca homeostasis and cardiac functions. Tumor necrosis factor-alpha (TNF-alpha) 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-alpha 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-alpha (1-50 ng/mL) was administered in HL-1 cardiomyocytes with and without co-administration of an NF-kappaB inhibitor (SN-50, 50 microg/mL), antioxidant agents (ascorbic acid, 100 microM, or coenzyme Q10, 10 microM), or methylation inhibitor (5-aza-2'-deoxycytidine, 0.1, 1 microM). MEASUREMENTS AND MAIN

RESULTS:

TNF-alpha (50 ng/mL) decreased the SERCA2a RNA and protein by quantitative polymerase chain reaction and immunoblot. Furthermore, TNF-alpha (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 microM). Additionally, TNF-alpha (50 ng/mL) increased the expression of DNA methyltransferase 1.

CONCLUSIONS:

TNF-alpha 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.
Asunto(s)

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Calcio / Factor de Necrosis Tumoral alfa / Miocitos Cardíacos / ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico Tipo de estudio: Diagnostic_studies Límite: Animals Idioma: En Año: 2010 Tipo del documento: Article

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Calcio / Factor de Necrosis Tumoral alfa / Miocitos Cardíacos / ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico Tipo de estudio: Diagnostic_studies Límite: Animals Idioma: En Año: 2010 Tipo del documento: Article