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Cardiovasc Res. 2015 Mar 1;105(3):318-29. doi: 10.1093/cvr/cvv008.

TNF-α down-regulates sarcoplasmic reticulum Ca²⁺ ATPase expression and leads to left ventricular diastolic dysfunction through binding of NF-κB to promoter response element.

Author information

1
Division of Cardiology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital Yun-Lin, No.579, Sec. 2, Yunlin Rd., Douliou City, Yunlin County 640, Taiwan Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan cttsai@ntuh.gov.tw cttsai1999@gmail.com.
2
Division of Cardiology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
3
Division of Cardiology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan.
4
Division of Cardiology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital Yun-Lin, No.579, Sec. 2, Yunlin Rd., Douliou City, Yunlin County 640, Taiwan Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
5
Division of Cardiology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan.
6
Division of Cardiology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.

Abstract

AIMS:

TNF-alpha (TNF-α) causes left ventricular diastolic dysfunction. Down-regulation of sarcoplasmic reticulum Ca(2+)-ATPase 2a protein (SERCA2a) expression is one of the major mechanisms underlying diastolic dysfunction. We investigated whether TNF-α modulates SERCA2a expression and alters cardiac diastolic function, and its detailed signalling pathway.

METHODS AND RESULTS:

We used both in vitro cellular cardiomyocyte model and in vivo rat model to address this issue. We found that TNF-α decreased the levels of both SERCA2a mRNA and protein in the cardiomyocytes, with corresponding impairment of diastolic calcium reuptake, a cellular phenotype of cardiac diastolic function. An ∼2 kb promoter of the SERCA2a gene (atp2a2) along with its serial deletions was cloned into the luciferase reporter system. TNF-α significantly decreased the promoter activity, and truncation of the SERCA2a gene promoter with the putative nuclear factor kappa-B (NF-κB) response element abolished TNF-α-induced SERCA2a gene suppression. Chromatin immunoprecipitation and gel retardation also confirmed the binding of NF-κB to this putative-binding site. TNF-α increased the phosphorylation of IKK and the degradation of IκB, resulted in NF-κB nuclear translocation, and decreased SERCA2a gene promoter activity. This process was attenuated by NF-κB blockers and simvastatin. In the in vivo rat model, lipopolysaccharide treatment significantly elevated the serum TNF-α level, as well as phosphorylation of IKK, resulting in a decrease in myocardial SERCA2a expression, diastolic calcium reuptake, and diastolic dysfunction. Oral treatment with simvastatin led to an increase in SERCA2a expression, alleviation, and prevention of the diastolic dysfunction.

CONCLUSIONS:

TNF-α suppresses SERCA2a gene expression via the IKK/IκB/NF-κB pathway and binding of NF-κB to the SERCA2a gene promoter, and its effect is blocked by simvastatin, demonstrating the potential therapeutic effect of statins in treating inflammation-related diastolic dysfunction.

KEYWORDS:

Diastolic dysfunction; SERCA2a; Simvastatin; TNF-α; Transcription; atp2a2

PMID:
25712896
DOI:
10.1093/cvr/cvv008
[Indexed for MEDLINE]

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