Receptors for many cardiac hormones and neurotransmitters are coupled to their effector enzymes and ion channels by a family of heterotrimeric GDP-binding proteins (G proteins made up of alpha and betagamma subunits. These proteins act as critical control points for directing signals initiated at the cell surface to specific intracellular second messenger pathways. They are essential for normal cardiac function, and their derangement in pathological states may contribute to abnormal responses of the heart to some agonists. In the past project period, we have created strains of transgenic mice carrying mutated G protein subunits targeted to the heart. One set of animals expressing a constitutively activated, HA epitope-tagged Galpha subunit (HAalpha/q*) develops cardiac hypertrophy, dilation and failure. Surprisingly, we found that expression of HAalpha/q* was transient, being present at 2 weeks in atria and ventricles, and becoming undetectable by 10 weeks of age. At 2 weeks of age when the product of the transgene is expressed, the hearts are essentially normal morphologically, but not functionally. This early transient expression of HAALPHA/q* causes pathological changes that continue and that worsen despite the fact that the level of HAalpha/q* drops. These mice provide a powerful, novel system in which to dissect primary from secondary changes leading to cardiac hypertrophy and eventually to failure. A major challenge is to define how changes that begin in the cardiomyocyte lead to changes in non-myocyte cells to produce the full-blown global cardiac pathology. Ultimately, the persistent pathology must be the result of persistent changes in the activity of sets of genes. A major long-term goal will be to use the system that we have developed to identify novel genes involved in the initiation and continuation of cardiac dilatation hypertrophy and the transition to failure, and to understand how changes in their function determine the pathology. Ultimately, the persistent pathology must be the result of persistent changes in the activity of sets of genes. A major long-term goal will be to use the system that we have developed to identify novel genes involved in the initiation and continuation of cardiac dilatation hypertrophy and the transition to failure, and to understand how changes in their function determine the pathology.
The Specific Aims are: 1) To define the mechanisms that link transient expression of constitutively activated alpha/1 in cardiac myocytes to persistent, fatal cardiac pathology. 2) To define the change in gene expression profile in cardiomyocytes from transgenic animals expressing HAalpha1* at an age when pathology is minimal and when it is severe. Transgenic animals will also be compared to age- and sex-matched wild-type animals. 3) To define the effect of increased alpha/1 signaling on development of hypertrophy through an independent pathway.
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