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Published on: April 22, 2010
Dominant-negative effect of a mutant cardiac troponin T on cardiac structure and function in transgenic mice
1Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
Insights
Mutant cardiac troponin T (cTnT) causes hypertrophic cardiomyopathy (HCM) by disrupting heart muscle structure and function. This study in mice demonstrates a dominant-negative effect leading to diastolic dysfunction and myocyte disarray.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Genetic Diseases
Background:
- Hypertrophic cardiomyopathy (HCM) is a genetic heart muscle disease.
- The underlying mechanisms of sarcomeric protein mutations in HCM remain unclear.
- A leading hypothesis suggests a dominant-negative effect of mutant proteins on myocyte function.
Purpose of the Study:
- To investigate the functional consequences of mutant human cardiac troponin T (cTnT) in vivo.
- To determine if mutant cTnT exerts a dominant-negative effect on cardiac structure and function.
- To establish a mouse model for studying HCM pathogenesis.
Main Methods:
- Generation of transgenic mice expressing normal (cTnT-Arg92) or mutant (cTnT-Gln92) human cTnT.
- Identification and characterization of transgenic lines using PCR and Southern blotting.
- Assessment of cardiac function via echocardiography and histological analysis of myocardial structure.
Main Results:
- Transgenic mice expressing mutant cTnT (cTnT-Gln92) exhibited diastolic dysfunction, indicated by a 50% reduction in the E/A ratio.
- Histological analysis revealed cardiac myocyte disarray (1-15% of myocardium) and a twofold increase in interstitial collagen in mutant mice.
- Normal cTnT transgene expression did not induce cardiac abnormalities.
Conclusions:
- Mutant cTnT-Gln92 exerts a dominant-negative effect on cardiac structure and function.
- This leads to myocyte disarray, increased collagen synthesis, and diastolic dysfunction in the heart.
- The findings support the dominant-negative hypothesis for HCM pathogenesis caused by sarcomeric protein mutations.
Abstract:
Hypertrophic cardiomyopathy (HCM) is a disease of sarcomeric proteins. The mechanism by which mutant sarcomeric proteins cause HCM is unknown. The leading hypothesis proposes that mutant sarcomeric proteins exert a dominant-negative effect on myocyte structure and function. To test this, we produced transgenic mice expressing low levels of normal or mutant human cardiac troponin T (cTnT). We constructed normal (cTnT-Arg92) and mutant (cTnT-Gln92) transgenes, driven by a murine cTnT promoter, and produced three normal and five mutant transgenic lines, which were identified by PCR and Southern blotting. Expression levels of the transgene proteins, detected using a specific antibody, ranged from 1 to 10% of the total cTnT pool. M-mode and Doppler echocardiography showed normal left ventricular dimensions and systolic function, but diastolic dysfunction in the mutant mice evidenced by a 50% reduction in the E/A ratio of mitral inflow velocities. Histological examination showed cardiac myocyte disarray in the mutant mice, which amounted to 1-15% of the total myocardium, and a twofold increase in the myocardial interstitial collagen content. Thus, the mutant cTnT-Gln92, responsible for human HCM, exerted a dominant-negative effect on cardiac structure and function leading to disarray, increased collagen synthesis, and diastolic dysfunction in transgenic mice.
