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. (19th February 2015)

• Record Type: Journal Article
• Authors: Tsai, Chia-Ti; Wu, Cho-Kai; Lee, Jen-Kuang; Chang, Sheng-Nan; Kuo, Yu-Min; Wang, Yi-Chih; Lai, Ling-Ping; Chiang, Fu-Tien; Hwang, Juey-Jen; Lin, Jiunn-Lee
• Is Part Of: Cardiovascular research. Volume 105:Number 3(2015)
• Page Start: 318
• Page End: 329
• Publication Date: 2015-02-19
• Subjects: TNF-α -- SERCA2a -- atp2a2 -- Transcription -- Diastolic dysfunction -- Simvastatin; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvv008
• Languages: English
• ISSNs: 0008-6363

Abstract

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.