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Translational mechanisms accelerate the rate of protein synthesis during canine pressure-overload hypertrophy
Y Nagatomo1, B A Carabello, M Hamawaki
1Department of Medicine and the Gazes Cardiac Research Institute, Medical University of South Carolina, and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29403, USA.
Insights
Cardiac protein synthesis accelerates during pressure overload through increased translational efficiency and capacity. This study in canines reveals how the heart adapts its protein production to sustained stress.
Area of Science:
- Cardiovascular Physiology
- Molecular Biology
- Cardiac Hypertrophy
Background:
- Cardiac pressure overload, such as from aortic stenosis (AS), leads to cardiac hypertrophy.
- Understanding the regulation of cardiac protein synthesis is crucial for addressing heart disease.
Purpose of the Study:
- To investigate the translational mechanisms governing cardiac protein synthesis during canine pressure overload.
- To determine how acute and sustained AS affects myosin heavy chain (MHC) synthesis and degradation.
Main Methods:
- Induction of acute and sustained aortic stenosis in canines.
- Measurement of left ventricular (LV) myosin heavy chain (MHC) synthesis using radiolabeled leucine infusion.
- Analysis of ribosomal RNA, total RNA, and MHC mRNA levels.
Main Results:
- Acute AS increased MHC synthesis rate via enhanced translational efficiency.
- Sustained AS led to increased total MHC synthesis and translational capacity, with elevated ribosome formation.
- MHC mRNA levels remained unchanged, indicating post-transcriptional regulation.
Conclusions:
- Cardiac protein synthesis is upregulated during pressure overload by initial increases in translational efficiency.
- Sustained hypertrophic growth involves adaptive increases in translational capacity.
- These mechanisms are key to the heart's response to chronic pressure overload.
Abstract:
This study examined how translational mechanisms regulate the rate of cardiac protein synthesis during canine pressure overload in vivo. Acute aortic stenosis (AS) was produced by inflating a balloon catheter in the ascending aorta for 6 h; sustained AS was created by controlled banding of the ascending aorta. AS caused significant hypertrophy as reflected by increased left ventricular (LV) mass after 5 and 10 days. To monitor LV protein synthesis in vivo, myosin heavy chain (MHC) synthesis was measured by continuous infusion of radiolabeled leucine. Acute AS accelerated the rate of myosin synthesis without a corresponding increase in ribosomal RNA, indicating an increase in translational efficiency. Total MHC synthesis (mg MHC/LV per day) was significantly increased at 5 and 10 days of sustained AS. Total MHC degradation was not significantly altered at 5 days of AS but increased at 10 days of AS in concordance with a new steady state with respect to growth. Translational capacity (mg total RNA/LV) was significantly increased after 5 and 10 days of AS and was preceded by an increase in the rate of ribosome formation. MHC mRNA levels remained unchanged during AS. These findings demonstrate that cardiac protein synthesis is accelerated in response to pressure overload by an initial increase in translational efficiency, followed by an adaptive increase in translational capacity during sustained hypertrophic growth.