title: Gene reprogramming in exercise-induced cardiac hypertrophy in swine: A transcriptional genomics approach.
abstract: Cardiac hypertrophy of the left ventricle (LV) in response to dynamic exercise-training (EX) is a beneficial adaptation to increased workload, and is thought to result from genetic reprogramming. We aimed to determine which transcription factors (TFs) are involved in this genetic reprogramming of the LV in swine induced by exercise-training. Swine underwent 3-6 weeks of dynamic EX, resulting in a 16% increase of LV weight/body weight ratio compared to sedentary animals (P=0.03). Hemodynamic analysis showed an increased stroke volume index (stroke volume/body weight +35%; P=0.02). Microarray-analysis of LV tissue identified 339 upregulated and 408 downregulated genes (false discovery rate<0.05). Of the human homologues of the differentially expressed genes, promoter regions were searched for TF consensus binding sites (TFBSs). For upregulated and downregulated genes, 17 and 24 TFBSs were overrepresented by >1.5-fold (P<0.01), respectively. In DNA-binding assays, using LV nuclear protein extracts and protein/DNA array, signal intensity changes >2-fold were observed for 23 TF-specific DNA probes. Matching results in TFBS and protein/DNA array analyses were obtained for transcription factors YY1 (Yin Yang 1), PAX6 (paired box 6) and GR (glucocorticoid receptor). Notably, PAX6 and GR show lower signals in TFBS and protein/DNA array analyses upon exercise-training, whereas we previously showed higher signals for these factors in the remodeled LV of swine post-myocardial infarction (MI). In conclusion, we have identified transcription factors that may drive the genetic reprogramming underlying exercise-training induced LV hypertrophy in swine. PAX6 and GR are among the transcription factors that are oppositely regulated in LV hypertrophy after exercise-training and MI. These proteins may be at the base of the differences between pathological and physiological hypertrophy.
authors.affiliation: Div. of Experimental Cardiology, Thoraxcenter, Cardiovascular research school COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands; Dept. of Biochemistry, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Diederik W D
authors.initials: DW
authors.lastname: Kuster
authors.affiliation: Div. of Experimental Cardiology, Thoraxcenter, Cardiovascular research school COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Daphne
authors.initials: D
authors.lastname: Merkus
authors.affiliation: Div. of Experimental Cardiology, Thoraxcenter, Cardiovascular research school COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Lau A
authors.initials: LA
authors.lastname: Blonden
authors.affiliation: Dept. of Bioinformatics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kremer
authors.affiliation: Center for Biomics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Wilfred F J
authors.initials: WF
authors.lastname: van IJcken
authors.affiliation: Dept. of Biochemistry, Erasmus University Medical Center, Rotterdam, The Netherlands; Division of Vascular and Metabolic Diseases, Dept. of Internal Medicine, Cardiovascular research school COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Adrie J M
authors.initials: AJ
authors.lastname: Verhoeven
authors.affiliation: Div. of Experimental Cardiology, Thoraxcenter, Cardiovascular research school COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands. Electronic address: d.duncker@erasmusmc.nl.
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Duncker
mesh_terms: D000818:Animals; D001665:Binding Sites; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005260:Female; D023281:Genomics; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010805:Physical Conditioning, Animal; D012420:Running; D017422:Sequence Analysis, DNA; D034421:Sus scrofa; D014157:Transcription Factors / Q000502:physiology; D059467:Transcriptome
chemical_list: D014157:Transcription Factors
keywords: Animal models of human disease; Cardiac hypertrophy; Exercise training; Microarray; Physiological hypertrophy; Transcription factors