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1 Department of Medicine, Beth Israel Deaconess Medical Center, and Division on Aging, Harvard Medical School, Boston, Massachusetts 02215; and 2 Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
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
-actin, skeletal -actin, -myosin heavy chain (-MHC), and
-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.
muscle genes; hypertrophy; transcription; serum response element; signaling
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