Acetylation mediates Cx43 reduction caused by electrical stimulation.
Communication between cardiomyocytes depends upon gap junctions (GJ). Previous studies have demonstrated that electrical stimulation induces GJ remodeling and modifies histone acetylase (HAT) and deacetylase (HDAC) activities, although these two results have not been linked. The aim of this work was to establish whether electrical stimulation modulates GJ-mediated cardiac cell-cell communication by acetylation-dependent mechanisms. Field stimulation of HL-1 cardiomyocytes at 0.5 Hz for 24 h significantly reduced connexin43 (Cx43) expression and cell-cell communication. HDAC activity was down-regulated whereas HAT activity was not modified resulting in increased acetylation of Cx43. Consistent with a post-translational mechanism, we did not observe a reduction in Cx43 mRNA in electrically stimulated cells, while the proteasomal inhibitor MG132 maintained Cx43 expression. Further, the treatment of paced cells with the HAT inhibitor Anacardic Acid maintained both the levels of Cx43 and cell-cell communication. Finally, we observed increased acetylation of Cx43 in the left ventricles of dogs subjected to chronic tachypacing as a model of abnormal ventricular activation. In conclusion, our findings suggest that altered electrical activity can regulate cardiomyocyte communication by influencing the acetylation status of Cx43.
Laboratory of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino IRCCS, Milano, Italy; Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), Bolzano Italy.
Viviana
V
Meraviglia
Laboratory of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino IRCCS, Milano, Italy; Department of Pharmacology, Chemotherapy and Medical Toxicology, Università degli Studi di Milano, Milano, Italy.
Valerio
V
Azzimato
Istituto di Patologia Medica, Università Cattolica del SacroCuore, Roma, Italy.
Claudia
C
Colussi
Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), Bolzano Italy.
Maria Cristina
MC
Florio
Department of Health Science, University of Milano Bicocca, Monza, Italy.
Anna
A
Binda
Department of Health Science, University of Milano Bicocca, Monza, Italy.
Alice
A
Panariti
Department of Physiology, New York Medical College, Valhalla, NY, United States.
Khaled
K
Qanud
Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), Bolzano Italy.
Silvia
S
Suffredini
Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), Bolzano Italy; Department of Life Sciences, University of Parma, Parma, Italy.
Laura
L
Gennaccaro
CERT, Center of Excellence for Toxicological Research, INAIL, ex ISPESL, University of Parma, Parma, Italy; Humanitas Clinical and Research Center, Rozzano Milano, Italy.
Michele
M
Miragoli
The PaceLab, Department of Biosciences, Università di Milano, Italy.
Andrea
A
Barbuti
Translational Research Program, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.
Paul D
PD
Lampe
Division of Cardiovascular Epigenetics, Department of Cardiology, Goethe University, Frankfurt am Main, Germany.
Carlo
C
Gaetano
Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), Bolzano Italy.
Peter P
PP
Pramstaller
Laboratory of Vascular Pathology, Istituto Dermopatico dell'Immacolata IRCCS, Roma, Italy.
Maurizio C
MC
Capogrossi
Department of Physiology, Temple University School of Medicine, Philadelphia, PA, United States; Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy.
Fabio A
FA
Recchia
Laboratory of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino IRCCS, Milano, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy.
Giulio
G
Pompilio
Department of Health Science, University of Milano Bicocca, Monza, Italy.
Ilaria
I
Rivolta
Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), Bolzano Italy. Electronic address: alessandra.rossini@eurac.edu.
Alessandra
A
Rossini
D000107:Acetylation / Q000187:drug effects; D048729:Anacardic Acids / Q000008:administration & dosage; D000818:Animals; D002450:Cell Communication / Q000235:genetics*; D018031:Connexin 43 / Q000096:biosynthesis* / Q000235:genetics; D004285:Dogs; D004558:Electric Stimulation; D017629:Gap Junctions / Q000235:genetics* / Q000473:pathology; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis
D048729:Anacardic Acids; D018031:Connexin 43; D012333:RNA, Messenger; C088115:anacardic acid; D051548:Histone Acetyltransferases; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1
Acetylation; Connexin43; Electrical field stimulation; Gap junctions