TY - JOUR
T1 - Orchestrated regulation of energy supply and energy expenditure
T2 - Transcriptional coexpression of metabolism, ion homeostasis, and sarcomeric genes in mammalian myocardium
AU - Barth, Andreas S.
AU - Kumordzie, Ami
AU - Tomaselli, Gordon F.
N1 - Publisher Copyright:
© 2016 Heart Rhythm Society. All rights reserved.
PY - 2016/5/1
Y1 - 2016/5/1
N2 - Background During the development of heart failure, the myocardium undergoes profound electrical remodeling, characterized by prolongation of action potential duration, changes in Ca2+ homeostasis, and slowing of conduction. Objective We tested the hypothesis that the electrical remodeling, indexed by the expression of ion channel and transporter genes, occurs in the context of a coordinated regulation of metabolism and signaling processes observed in heart failure. Methods A meta-analysis of myocardial murine and human microarray data sets was performed. Results We identified transcripts that were coordinately expressed with 132 myocardial ion channel and transporter genes in 18 murine and human myocardial microarray data sets. The genes coexpressed with ion channels were subsequently grouped into Gene Ontology (GO) categories, revealing 4 major, mutually exclusive GO clusters: 55 ion channel and transporter genes were coexpressed with major bioenergetic pathways (oxidative phosphorylation, citric acid cycle, glycolysis, and fatty acid metabolism) and contractile processes (muscle contraction, sarcomere, and Z disc), while 36, 16, and 25 ion channel transcripts were associated with the GO clusters of signal transduction, transcription/translation, and a nonspecified cluster, respectively. Myocardial expression of ion channel genes coexpressed with metabolic processes was >10-fold higher than that of ion channels associated with the other 3 clusters. In addition to transcriptional coexpression, major myocardial ion channels were found to physically interact with metabolic pathways based on protein-protein interaction data. Conclusion Electromechanical and metabolic remodeling processes are intricately linked at the transcriptional level, suggesting an orchestrated regulation of energy supply (metabolism) and energy expenditure (muscle contraction and ion homeostasis) in mammalian myocardium.
AB - Background During the development of heart failure, the myocardium undergoes profound electrical remodeling, characterized by prolongation of action potential duration, changes in Ca2+ homeostasis, and slowing of conduction. Objective We tested the hypothesis that the electrical remodeling, indexed by the expression of ion channel and transporter genes, occurs in the context of a coordinated regulation of metabolism and signaling processes observed in heart failure. Methods A meta-analysis of myocardial murine and human microarray data sets was performed. Results We identified transcripts that were coordinately expressed with 132 myocardial ion channel and transporter genes in 18 murine and human myocardial microarray data sets. The genes coexpressed with ion channels were subsequently grouped into Gene Ontology (GO) categories, revealing 4 major, mutually exclusive GO clusters: 55 ion channel and transporter genes were coexpressed with major bioenergetic pathways (oxidative phosphorylation, citric acid cycle, glycolysis, and fatty acid metabolism) and contractile processes (muscle contraction, sarcomere, and Z disc), while 36, 16, and 25 ion channel transcripts were associated with the GO clusters of signal transduction, transcription/translation, and a nonspecified cluster, respectively. Myocardial expression of ion channel genes coexpressed with metabolic processes was >10-fold higher than that of ion channels associated with the other 3 clusters. In addition to transcriptional coexpression, major myocardial ion channels were found to physically interact with metabolic pathways based on protein-protein interaction data. Conclusion Electromechanical and metabolic remodeling processes are intricately linked at the transcriptional level, suggesting an orchestrated regulation of energy supply (metabolism) and energy expenditure (muscle contraction and ion homeostasis) in mammalian myocardium.
KW - Arrhythmia
KW - Gene expression
KW - Heart failure
KW - Ion channels
KW - Metabolism
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U2 - 10.1016/j.hrthm.2016.01.009
DO - 10.1016/j.hrthm.2016.01.009
M3 - Article
C2 - 26776558
AN - SCOPUS:84960172271
SN - 1547-5271
VL - 13
SP - 1131
EP - 1139
JO - Heart Rhythm
JF - Heart Rhythm
IS - 5
ER -