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Myofibrillar protein turnover in cardiac hypertrophy due to aortic regurgitation
N M Magid1, D C Wallerson, J S Borer
1Department of Medicine, Cornell University Medical College, New York Hospital-Cornell Medical Center, N.Y. 10021.
Insights
Cardiac hypertrophy from aortic regurgitation involves decreased protein degradation, not increased synthesis, for myofibrillar proteins. Protein synthesis contributes only to early stages; sustained growth relies on reduced degradation.
Area of Science:
- Cardiovascular Biology
- Molecular Physiology
- Cardiac Remodeling
Background:
- Progressive cardiac hypertrophy is a hallmark of chronic aortic regurgitation.
- Previous studies indicated reduced protein degradation, not synthesis, drives overall cardiac growth in this model.
Purpose of the Study:
- To investigate the specific roles of synthesis and degradation of individual myofibrillar proteins in left ventricular hypertrophy due to aortic regurgitation.
- To differentiate the contributions of protein synthesis and degradation to early versus sustained cardiac hypertrophy.
Main Methods:
- Rabbits underwent surgical induction of aortic regurgitation or sham operation.
- Fractional synthesis rates of actin, myosin light chains, alpha-actinin, and desmin were measured using [3H]-leucine infusions.
- Protein concentrations, echocardiography, and ventricular weights determined growth and degradation rates.
Main Results:
- Myofibrillar protein content increased rapidly in the first week, then slowed, paralleling left ventricular weight gain.
- Fractional synthesis rates were elevated at 3 days post-surgery but normalized by 1 month.
- Sustained cardiac hypertrophy at 1 month was primarily attributed to decreased myofibrillar protein fractional degradation rates.
Conclusions:
- Early cardiac myocyte hypertrophy involves increased myofibrillar protein synthesis.
- Progressive and sustained left ventricular hypertrophy in chronic aortic regurgitation is predominantly driven by suppressed myofibrillar protein degradation.
- Understanding these distinct mechanisms is crucial for targeting therapeutic interventions in heart failure.
Abstract:
We recently demonstrated that total cardiac protein and myosin heavy chain fractional synthesis rates were not increased during the progressive cardiac hypertrophy that occurred 1 month following induction of aortic regurgitation. The increase in total cardiac protein and myosin heavy chain observed after 1 month of chronic volume overload was caused by a decrease in protein fractional degradation rates. The objective of the present study was to determine in vivo the relative contributions of protein synthesis and degradation of a variety of individual myofibrillar protein constituents, other than myosin heavy chain, to the left ventricular hypertrophic response to chronic aortic regurgitation. Intravenous infusions of [3H]-leucine were administered 3 days and 1 month following surgical induction of aortic regurgitation and sham operation in rabbits, and actin, myosin light chains 1 and 2, alpha-actinin and desmin fractional synthesis rates were obtained by analysis of plasma and protein hydrolysate data using [14C]-dansyl chloride assays. Individual myofibrillar protein growth rates were determined from protein concentration and serial echocardiographic and postmortem left ventricular weight measurements; protein degradation rates were determined by subtraction of growth rates from synthesis rates. Individual myofibrillar protein content increased most rapidly during the 1st week and progressively increased at a slower rate between 1 week and 1 month, in parallel with increases in left ventricular weight. In comparison with sham-operated controls, individual myofibrillar protein fractional synthesis rates were consistently increased at 3 days but not at 1 month. Progressive myocyte hypertrophy occurring at 1 month was caused by a decrease in myofibrillar protein fractional degradation rates. Increased myofibrillar protein synthesis contributed only to the early phase of myocyte hypertrophy while progressive hypertrophy in chronic aortic regurgitation was due to suppression of myofibrillar protein degradation.