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Published on: June 3, 2018
Cardiomyopathy in transgenic mice with cardiac-specific overexpression of serum response factor
1Department of Medicine, Beth Israel Deaconess Medical Center, and Division on Aging, Harvard Medical School, Boston, Massachusetts 02215, USA.
Abstract:
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.
Insights
Overexpressing serum response factor (SRF) in the heart causes cardiomyopathy and cardiac dysfunction in mice. This suggests SRF plays a key role in regulating cardiac structure and function.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Gene Regulation
Background:
- Serum response factor (SRF) is a MADS-family transcription factor involved in cardiac gene regulation.
- SRF influences genes critical for cardiac muscle function, such as alpha-actin and myosin heavy chains.
- The precise in vivo role of SRF in maintaining cardiac function requires further elucidation.
Purpose of the Study:
- To investigate the in vivo consequences of cardiac-specific SRF overexpression.
- To test the hypothesis that elevated SRF levels impact cardiac morphology and function.
- To understand SRF's role in cardiac hypertrophy pathways.
Main Methods:
- Generation of transgenic mice with cardiac-specific overexpression of the human SRF gene.
- Assessment of cardiac morphology via heart weight-to-body weight ratio and echocardiography.
- Histological analysis including cardiomyocyte size, collagen deposition, and fibrosis.
- Evaluation of SRF-regulated gene expression and cardiac function.
Main Results:
- Transgenic mice exhibited significant cardiac changes, including cardiomyopathy, increased heart weight, and four-chamber dilation.
- Histological findings revealed cardiomyocyte hypertrophy, collagen deposition, and interstitial fibrosis.
- SRF overexpression led to altered expression of target genes and impaired cardiac muscle function.
Conclusions:
- Sustained cardiac overexpression of SRF is sufficient to induce cardiac remodeling and dysfunction, even without other stimuli.
- SRF is implicated as a key downstream mediator in signaling pathways that drive cardiac hypertrophy.
- These findings highlight SRF's critical role in maintaining normal cardiac structure and function.
