Myocardin induces cardiomyocyte hypertrophy.
In response to stress signals, postnatal cardiomyocytes undergo hypertrophic growth accompanied by activation of a fetal gene program, assembly of sarcomeres, and cellular enlargement. We show that hypertrophic signals stimulate the expression and transcriptional activity of myocardin, a cardiac and smooth muscle-specific coactivator of serum response factor (SRF). Consistent with a role for myocardin as a transducer of hypertrophic signals, forced expression of myocardin in cardiomyocytes is sufficient to substitute for hypertrophic signals and induce cardiomyocyte hypertrophy and the fetal cardiac gene program. Conversely, a dominant-negative mutant form of myocardin, which retains the ability to associate with SRF but is defective in transcriptional activation, blocks cardiomyocyte hypertrophy induced by hypertrophic agonists such as phenylephrine and leukemia inhibitory factor. Myocardin-dependent hypertrophy can also be partially repressed by histone deacetylase 5, a transcriptional repressor of myocardin. These findings identify myocardin as a nuclear effector of hypertrophic signaling pathways that couples stress signals to a transcriptional program for postnatal cardiac growth and remodeling.
Xing
Weibing
W
Carolina Cardiovascular Biology Center, Department of Cell and Developmental Biology, University of North Carolina, Chapel Hill, NC 27599-7126, USA.
Zhang
Tong-Cun
TC
Cao
Dongsun
D
Wang
Zhigao
Z
Antos
Christopher L
CL
Li
Shijie
S
Wang
Yibin
Y
Olson
Eric N
EN
Wang
Da-Zhi
DZ
D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000503:physiopathology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006321:Heart / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032342:Muscle Cells / Q000166:cytology* / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D026362:Serum Response Factor / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D000099251:Myocardin
D009687:Nuclear Proteins; D026362:Serum Response Factor; D015534:Trans-Activators; D000099251:Myocardin