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Alteration of Ca2+ release channel function in sarcoplasmic reticulum of pressure-overload-induced hypertrophic rat
1Department of Medicine, University of Connecticut Health Center, Farmington 06030-1305.
Insights
Pressure-overload left ventricular hypertrophy alters the function of the calcium (Ca2+) release channel in the sarcoplasmic reticulum. This study reveals changes in channel density and increased sensitivity to agonists, impacting cardiac calcium handling.
Area of Science:
- Cardiology
- Molecular Biology
- Physiology
Background:
- Left ventricular hypertrophy (LVH) is a cardiac condition often caused by pressure overload.
- The sarcoplasmic reticulum (SR) plays a critical role in regulating intracellular calcium (Ca2+) levels, essential for heart muscle contraction.
- Dysfunctional Ca2+ release channels in the SR are implicated in various cardiac pathologies.
Purpose of the Study:
- To investigate the impact of pressure-overload induced LVH on the Ca2+ release channel within the cardiac sarcoplasmic reticulum.
- To characterize any quantitative or qualitative alterations in the Ca2+ release channel function in the hypertrophied left ventricle.
Main Methods:
- Utilized [3H]ryanodine binding assays to quantify Ca2+ release channel density in left ventricular homogenates and SR vesicles.
- Employed 45Ca2+ flux measurements to assess Ca2+ release from isolated SR vesicles.
- Examined the effects of Ca2+ release agonists like caffeine and doxorubicin on channel activity.
Main Results:
- A significant decrease in the density (Bmax) of Ca2+ release channels was observed in hypertrophied left ventricles compared to sham controls.
- The total number of Ca2+ release channels in the whole left ventricle remained similar between groups.
- SR yield was reduced in hypertrophied ventricles, and the Ca2+ release channels exhibited increased sensitivity to agonists.
Conclusions:
- Pressure-overload induced LVH is associated with quantitative changes, specifically reduced Ca2+ release channel density in the left ventricle.
- Qualitative alterations, including enhanced channel sensitivity to agonists, were also identified.
- These functional modifications in the Ca2+ release channel likely contribute to altered cardiac calcium handling in LVH.
Abstract:
The effects of pressure-overload left ventricular hypertrophy on the Ca2+ release channel in sarcoplasmic reticulum (SR) were studied by [3H]ryanodine binding and 45Ca2+ flux measurements. The density of Ca2+ release channel in left ventricle determined by equilibrium [3H]ryanodine binding to whole homogenates was significantly lower in hypertrophy than sham (Bmax: 0.47 +/- 0.04 v 0.72 +/- 0.10 pmol/mg protein), whereas total number of Ca2+ release channels in whole left ventricle was similar in the two groups. Ryanodine binding to SR vesicles isolated by differential centrifugation was also similar in the two groups, but the SR yield was less in the hypertrophied left ventricle. The Ca2+ release channels in hypertrophied left ventricles showed a significantly increased sensitivity to Ca2+ release agonists (e.g. caffeine and doxorubicin), as characterized by the effects of these agonists on ryanodine binding to whole homogenates and Ca2+ release from isolated SR. These results indicate that pressure-overload left ventricular hypertrophy is associated with both qualitative and quantitative changes in Ca2+ release channel function.