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Alterations in cardiac SR Ca(2+)-release channels during development of heart failure in cardiomyopathic hamsters
T Ueyama1, T Ohkusa, Y Hisamatsu
1Second Department of Internal Medicine, Yamaguchi University School of Medicine, Japan.
Insights
In cardiomyopathic hamsters, the number of ryanodine receptors (RyR) initially increased but later decreased as heart failure progressed, impacting cardiac function. This suggests RyR levels change dynamically during heart disease development.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Animal Models of Disease
Background:
- Syrian hamsters with UM-X7.1 mutation develop progressive cardiomyopathy, mirroring human heart failure.
- Cardiac dysfunction involves cellular necrosis, hypertrophy, dilatation, and eventual congestive heart failure.
Purpose of the Study:
- To investigate changes in cardiac mechanical function.
- To quantify sarcoplasmic reticulum (SR) Ca(2+)-release channels (ryanodine receptors, RyR) content during heart failure progression in UM-X7.1 hamsters.
Main Methods:
- Equilibrium binding assays using [3H]ryanodine to determine RyR binding site density (Bmax).
- Quantitative immunoblot assays to measure RyR protein levels.
- Assessment of cardiac function in hamsters at 8, 18, and 28 weeks of age.
Main Results:
- UM-X7.1 hamsters showed left ventricular hypertrophy by 8 weeks and dilatation by 18-28 weeks.
- Cardiac function was impaired by 18 weeks, with global hypokinesis at later stages.
- RyR protein content initially increased but significantly decreased below normal levels by 28 weeks as heart failure advanced.
Conclusions:
- RyR levels were preserved during early hypertrophy and heart failure stages, possibly with compensatory protein upregulation.
- A decline in RyR number occurs as heart failure becomes advanced.
- These dynamic changes in RyR content may contribute to the progressive cardiac dysfunction observed in this model.
Abstract:
The cardiomyopathic Syrian hamster develops a progressive cardiomyopathy characterized by cellular necrosis, hypertrophy, cardiac dilatation, and congestive heart failure. This study aimed to identify alterations in cardiac mechanical function and in the cellular content of sarcoplasmic reticulum (SR) Ca(2+)-release channels (ryanodine receptors, RyR) in the heart of the UM-X7.1 cardiomyopathic hamster during the development of heart failure. Experimental and healthy control hamsters were examined at 8, 18, and 28 wk of age. The UM-X7.1 hamsters had developed left ventricular (LV) hypertrophy at 8 wk and a marked LV dilatation at 18-28 wk. During the latter stage, the UM-X7.1 hamster hearts showed global hypokinesis. Equilibrium binding assays of high-affinity sites for [3H]ryanodine were performed in ventricular homogenate preparations. There was no significant difference between the two groups in the maximum number of [3H]ryanodine binding sites (Bmax) at either 8 or 18 wk of age, although the cardiac pump function was impaired in UM-X7.1 hamsters at 18 wk of age. By 28 wk, Bmax was significantly lower in the UM-X7.1 hamsters. Quantitative immunoblot assay revealed that the content of RyR protein in cardiomyopathic hearts, which was increased at the early stage, declined to below normal as heart failure advanced. These results suggest that the number of RyR in the UM-X7.1 cardiomyopathic hamsters was preserved at both the hypertrophic and early stages of heart failure with a possibly compensatory increase in the level of protein expression, although the cardiac function already showed a tendency to be impaired.