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Assessment of Sarcoplasmic Reticulum Calcium Reserve and Intracellular Diastolic Calcium Removal in Isolated Ventricular Cardiomyocytes
Published on: September 18, 2017
Sodium accumulation promotes diastolic dysfunction in end-stage heart failure following Serca2 knockout
William E Louch1, Karina Hougen, Halvor K Mørk
1Institute for Experimental Medical Research, Oslo University Hospital Ullevaal, 0407 Oslo, Norway. w.e.louch@medisin.uio.no
The Journal of Physiology
|December 17, 2009
Summary
Heart failure involves impaired calcium handling. Loss of SR Ca(2+)-ATPase (SERCA) causes systolic and diastolic dysfunction, but preventing sodium buildup can preserve diastolic function.
Area of Science:
- Cardiology
- Molecular Biology
- Physiology
Background:
- Calcium (Ca2+) flux alterations in cardiomyocytes contribute to heart failure.
- The sarcoplasmic reticulum Ca2+-ATPase (SERCA) is crucial for regulating intracellular Ca2+ levels.
Purpose of the Study:
- To investigate the mechanisms of heart failure progression in mice lacking cardiomyocyte-specific SERCA.
- To understand the roles of Ca2+ fluxes and sodium handling in cardiac dysfunction.
Main Methods:
- Conditional, cardiomyocyte-specific excision of the SERCA gene in mice.
- Assessment of cardiac function, myocyte contractility, and Ca2+ transients at 4 and 7 weeks post-gene deletion.
- Analysis of ion channel activity, including L-type Ca2+ current and Na+-Ca2+ exchange (NCX).
Main Results:
- SERCA gene deletion led to near-normal cardiac function at 4 weeks but end-stage heart failure by 7 weeks.
- Reduced myocyte contraction and slowed relaxation correlated with impaired Ca2+ transients and loss of SR Ca2+ release.
- Increased L-type Ca2+ current and enhanced Na+-Ca2+ exchange partially compensated for SERCA loss.
- Sodium accumulation due to reduced Na+-K+-ATPase activity impaired Na+-Ca2+ exchange-mediated Ca2+ extrusion, worsening diastolic dysfunction.
Conclusions:
- SERCA loss is a primary driver of systolic and diastolic dysfunction in this heart failure model.
- Cytosolic sodium accumulation exacerbates diastolic dysfunction by hindering Ca2+ extrusion.
- Preventing sodium gain may preserve diastolic function even with SERCA deficiency.
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