title: Transcription Factor CREM Mediates High Glucose Response in Cardiomyocytes and in a Male Mouse Model of Prolonged Hyperglycemia.
abstract: This study aims at investigating the epigenetic landscape of cardiomyocytes exposed to elevated glucose levels. High glucose (30 mM) for 72 hours determined some epigenetic changes in mouse HL-1 and rat differentiated H9C2 cardiomyocytes including upregulation of class I and III histone deacetylase protein levels and activity, inhibition of histone acetylase p300 activity, increase in histone H3 lysine 27 trimethylation, and reduction in H3 lysine 9 acetylation. Gene expression analysis focused on cardiotoxicity revealed that high glucose induced markers associated with tissue damage, fibrosis, and cardiac remodeling such as Nexilin (NEXN), versican, cyclic adenosine 5'-monophosphate-responsive element modulator (CREM), and adrenoceptor α2A (ADRA2). Notably, the transcription factor CREM was found to be important in the regulation of cardiotoxicity-associated genes as assessed by specific small interfering RNA and chromatin immunoprecipitation experiments. In CD1 mice, made hyperglycemic by streptozotoicin (STZ) injection, cardiac structural alterations were evident at 6 months after STZ treatment and were associated with a significant increase of H3 lysine 27 trimethylation and reduction of H3 lysine 9 acetylation. Consistently, NEXN, CREM, and ADRA2 expression was significantly induced at the RNA and protein levels. Confocal microscopy analysis of NEXN localization showed this protein irregularly distributed along the sarcomeres in the heart of hyperglycemic mice. This evidence suggested a structural alteration of cardiac Z-disk with potential consequences on contractility. In conclusion, high glucose may alter the epigenetic landscape of cardiac cells. Sildenafil, restoring guanosine 3', 5'-cyclic monophosphate levels, counteracted the increase of CREM and NEXN, providing a protective effect in the presence of hyperglycemia.
authors.affiliation: Institute of Human Physiology, Università Cattolica di Roma, 00168 Rome, Italy.|Institute of Medical Pathology, Università Cattolica di Roma, 00168 Rome, Italy.
authors.forename: Saviana A
authors.initials: SA
authors.lastname: Barbati
authors.affiliation: Institute of Medical Pathology, Università Cattolica di Roma, 00168 Rome, Italy.|Institute of Cell Biology and Neurobiology, National Research Council, 00143 Rome, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Colussi
authors.affiliation: Institute of Medical Pathology, Università Cattolica di Roma, 00168 Rome, Italy.
authors.forename: Lorenza
authors.initials: L
authors.lastname: Bacci
authors.affiliation: Institute of Medical Pathology, Università Cattolica di Roma, 00168 Rome, Italy.|Institute of Cell Biology and Neurobiology, National Research Council, 00143 Rome, Italy.
authors.forename: Aurora
authors.initials: A
authors.lastname: Aiello
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, 00143 Rome, Italy.
authors.forename: Agnese
authors.initials: A
authors.lastname: Re
authors.affiliation: Department of Histopathology, Università Cattolica di Roma, 00168 Rome, Italy.
authors.forename: Egidio
authors.initials: E
authors.lastname: Stigliano
authors.affiliation: Department of Experimental Medicine, "Sapienza" University, 00161 Rome, Italy.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Isidori
authors.affiliation: Institute of Human Physiology, Università Cattolica di Roma, 00168 Rome, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Grassi
authors.affiliation: Institute of Medical Pathology, Università Cattolica di Roma, 00168 Rome, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Pontecorvi
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, 00143 Rome, Italy.|Medicine Clinic III, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany.
authors.forename: Antonella
authors.initials: A
authors.lastname: Farsetti
authors.affiliation: Medicine Clinic III, Division of Cardiovascular Epigenetics, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany.
authors.forename: Carlo
authors.initials: C
authors.lastname: Gaetano
authors.affiliation: Institute of Medical Pathology, Università Cattolica di Roma, 00168 Rome, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Nanni
mesh_terms: D000818:Animals; D066126:Cardiotoxicity / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D051786:Cyclic AMP Response Element Modulator / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D005947:Glucose / Q000009:adverse effects* / Q000378:metabolism*; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D013997:Time Factors
chemical_list: C497411:Crem protein, mouse; D051786:Cyclic AMP Response Element Modulator; D005947:Glucose