Cardiomyopathy in transgenic mice with cardiac-specific overexpression of serum response factor.
Serum response factor (SRF), a member of the MCM1, agamous, deficiens, SRF (MADS) family of transcriptional activators, has been implicated in the transcriptional control of a number of cardiac muscle genes, including cardiac alpha-actin, skeletal alpha-actin, alpha-myosin heavy chain (alpha-MHC), and beta-MHC. To better understand the in vivo role of SRF in regulating genes responsible for maintenance of cardiac function, we sought to test the hypothesis that increased cardiac-specific SRF expression might be associated with altered cardiac morphology and function. We generated transgenic mice with cardiac-specific overexpression of the human SRF gene. The transgenic mice developed cardiomyopathy and exhibited increased heart weight-to-body weight ratio, increased heart weight, and four-chamber dilation. Histological examination revealed cardiomyocyte hypertrophy, collagen deposition, and interstitial fibrosis. SRF overexpression altered the expression of SRF-regulated genes and resulted in cardiac muscle dysfunction. Our results demonstrate that sustained overexpression of SRF, in the absence of other stimuli, is sufficient to induce cardiac change and suggest that SRF is likely to be one of the downstream effectors of the signaling pathways involved in mediating cardiac hypertrophy.
Zhang
X
X
Department of Medicine, Beth Israel Deaconess Medical Center, and Division on Aging, Harvard Medical School, Boston, Massachusetts 02215, USA.
Azhar
G
G
Chai
J
J
Sheridan
P
P
Nagano
K
K
Brown
T
T
Yang
J
J
Khrapko
K
K
Borras
A M
AM
Lawitts
J
J
Misra
R P
RP
Wei
J Y
JY
D000199:Actins / Q000235:genetics*; D000375:Aging; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D015152:Blotting, Northern; D009202:Cardiomyopathies / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D016189:Dystrophin / Q000235:genetics; D004452:Echocardiography; D018507:Gene Expression Regulation, Developmental; D016762:Genes, fos; D016758:Genes, jun; D006321:Heart / Q000254:growth & development / Q000502:physiology* / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics; D026362:Serum Response Factor; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016277:Ventricular Function, Left
D000199:Actins; D004268:DNA-Binding Proteins; D016189:Dystrophin; D009687:Nuclear Proteins; D020033:Protein Isoforms; D026362:Serum Response Factor; D014157:Transcription Factors; D009320:Atrial Natriuretic Factor; D018995:Myosin Heavy Chains