ATPase expression and leads to left ventricular diastolic dysfunction through binding of NF-kB to promoter response element

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We used both in vitro cellular cardiomyocyte model and in vivo rat model to address this issue. We found that TNF-a 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)alongwithitsserialdeletionswasclonedintotheluciferasereportersystem.TNF-asignificantlydecreased the promoteractivity,and truncation of the SERCA2a gene promoter with the putativenuclear factor kappa-B(NF-kB) response element abolished TNF-a-induced SERCA2a gene suppression. Chromatin immunoprecipitation and gel retardation also confirmed the binding of NF-kB to this putative-binding site. TNF-a increased the phosphorylation of IKKandthedegradationofIkB,resultedinNF-kBnucleartranslocation,anddecreasedSERCA2agenepromoteractivity. This process was attenuated by NF-kB blockers and simvastatin. In the in vivo rat model, lipopolysaccharide treatment significantly elevated the serum TNF-a 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-asuppressesSERCA2ageneexpressionviatheIKK/IkB/NF-kBpathwayandbindingofNF-kBtotheSERCA2agene promoter, and its effect is blocked by simvastatin, demonstrating the potential therapeutic effect of statins in treating inflammation-related diastolic dysfunction. TNF-a † SERCA2a † atp2a2 † Transcription † Diastolic dysfunction † Simvastatin

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