TY - JOUR
T1 - Gene reprogramming in exercise-induced cardiac hypertrophy in swine: A transcriptional genomics approach
AU - Kuster, Diederik
AU - Merkus, Daphne
AU - Blonden, Lau
AU - Kremer, Andreas
AU - van Ijcken, Wilfred
AU - Verhoeven, Adrie
AU - Duncker, Dirk-jan
PY - 2014
Y1 - 2014
N2 - 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. (C) 2014 Elsevier Ltd. All rights reserved.
AB - 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. (C) 2014 Elsevier Ltd. All rights reserved.
U2 - 10.1016/j.yjmcc.2014.10.006
DO - 10.1016/j.yjmcc.2014.10.006
M3 - Article
C2 - 25451387
SN - 0022-2828
VL - 77
SP - 168
EP - 174
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
ER -