Abstract 13238: C/ebpb Controls Cardiac Growth During Exercise
Background: Cardiomyocytes grow in size in response to physiological and pathological stimuli. Several transcriptional pathways regulating pathological hypertrophy have been described, but the molecular mechanisms underlying physiological growth remains somewhat elusive.
Aim/Methods: We hypothesized that one or more transcription factors control physiological hypertrophy. We therefore used a novel, qPCR based screen (Quanttrx) to systematically assess expression of all known and predicted transcriptional factors (∼1950 genes) in hearts of mice subjected to 2 weeks of intensive exercise (n=4) in comparison to unexercised littermates (n=4).
Results: Exercise produced a 32% increase in cardiac mass (Heart weight/tibial length=10.4±0.59 vs 7.9±0.64, p<0,05). Using Quanttrx, we identified C/EBPb as a cardiomyocyte-enriched transcription factor that was down regulated to 50% with endurance exercise, and confirmed this by RT-PCR and immunoblotting. SiRNA knockdown of C/EBPb in vitro increased cardiomyocyte size (45±12% n=3 and three experiments, p<0.05) and 11/19 transcription factors altered in the exercise model were also regulated to a similar degree by C/EBPb reduction in vitro (p<0.01 Chi Square). A plausible mechanistic explanation for the transcriptional regulation was found via a direct interaction with Serum Response Factor (SRF) that inhibited its DNA binding in ChIP studies. We used heterozygous C/EBPb null mice to assay effects of reduced C/EBPb in vivo. At baseline, C/EBPb+/− mice manifested a small increase in cardiomyocyte size (15±5%, n=6, p=0.035) and increased exercise capacity (1.05±0.05 Watts vs 0.065±0.06 in wild type, p=0.012). After transverse aortic constriction (TAC), C/EBPb+/− had better cardiac function than wild-type littermates as judged from echocardiographic fractional shortening (54±8% vs 36±4%, 45 days post-TAC, p=0.044).
Conclusion: Taken together, these data demonstrate an exercise-induced pathway dependent on C/EBPb which promotes physiological growth and protects cardiomyocytes from pathological stimuli.
- © 2010 by American Heart Association, Inc.