Related Experiment Videos
[Molecular basis for cardiac functions]
R Nagai1, T Yamazaki, I Shiojima
13rd Department of Internal Medicine, University of Tokyo.
Insights
This study reveals molecular changes in cardiac hypertrophy, showing increased protein synthesis and altered myosin heavy chain (MHC) expression. It also details decreased sarcoplasmic reticulum Ca(2+)-ATPase activity, crucial for heart relaxation.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Cellular Physiology
Background:
- Cardiac hypertrophy involves alterations in contractile and calcium regulatory proteins.
- Impaired contractile and diastolic functions are linked to these molecular changes.
- Understanding these adaptations is key to treating heart conditions.
Purpose of the Study:
- To analyze molecular changes during the development of cardiac hypertrophy.
- To investigate alterations in protein synthesis, myosin heavy chain (MHC) isoforms, and sarcoplasmic reticulum Ca(2+)-ATPase (SR Ca(2+)-ATPase).
- To explore signal transduction pathways involved in cardiac myocyte adaptation.
Main Methods:
- Cardiac hypertrophy induced via pulmonary artery constriction (rabbits) or aortic constriction (rats).
- Analysis of protein synthesis, MHC isoform expression (mRNA and protein levels).
- Measurement of SR Ca(2+)-ATPase activity and mRNA levels.
- Investigation of signal transduction by stretching cardiac myocytes.
Main Results:
- Protein synthesis increased significantly (1.8x) in rabbit ventricular hypertrophy.
- A shift from alpha-MHC to beta-MHC expression occurred at the mRNA level.
- SR Ca(2+)-ATPase activity and mRNA levels decreased in pressure-overload hypertrophy but increased in thyrotoxic hearts.
- Stretching myocytes activated protein kinase C, MAP-II kinase, and S6 kinase, potentially inducing fetal-type genes.
Conclusions:
- Cardiac hypertrophy involves complex molecular adaptations in protein synthesis and contractile elements.
- Downregulation of SR Ca(2+)-ATPase impairs relaxation in hypertrophied hearts.
- Signal transduction pathways play a role in mediating hypertrophic responses and gene expression changes.
Abstract:
Cardiac functions are regulated by both contractile proteins and calcium regulatory proteins. Alterations of these are considered involved in impaired contractile and diastolic functions in hypertrophied hearts. In this study, we analyzed molecular changes during the development of cardiac hypertrophy. Cardiac hypertrophy was induced by constricting the pulmonary artery in rabbits or the aorta in rats. In rabbit right ventricular hypertrophy, protein synthesis was increased to 1.8 times the control 2-4 days after pulmonary constriction. This increase in protein synthesis could be classified as an increase in both capacity and efficiency of synthesis. beta-cardiac myosin heavy chain (beta-MHC) isoform was predominantly expressed and alpha-MHC was suppressed in pressure overload hypertrophy. The switch from alpha- to beta-MHC occurred at the mRNA level. Ca(2+)-ATPase of sarcoplasmic reticulum (SR) is important because it regulates intracellular Ca2+ levels during relaxation. In pressure-overload hypertrophy, the SR Ca(2+)-ATPase was markedly decreased in both the enzyme activities and mRNA levels, while in thyrotoxic hearts both were increased. Interstitial cells also undergo phenotypic modulation which was demonstrated by the induction of nonmuscle-type MHC in pressure-overload hypertrophy. The signal transduction system in cardiac hypertrophy was examined by stretching cardiac myocytes grown on deformable membranes. In our analysis, stretching myocytes stimulated protein kinase C, MAP-II kinase and S6 kinase, all of which may lead to the induction of fetal-type cardiac genes and accelerated protein synthesis. These analyses of subcellular adaptation in cardiac hypertrophy provide important insights into understanding molecular mechanisms of cardiac functions.