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Regulation of expression of cardiac sarcoplasmic reticulum proteins under pathophysiological conditions
1University of California, San Diego, La Jolla 92093, USA.
Insights
Increased expression of the SERCA2 gene enhances cardiac function. This study found improved systolic contraction and diastolic relaxation in transgenic mice and cardiac cells, suggesting a therapeutic target for heart failure.
Area of Science:
- Cardiology
- Molecular Biology
- Biochemistry
Background:
- Congestive heart failure is a major health issue.
- Slow diastolic relaxation in heart failure may involve reduced sarcoplasmic reticulum Ca2+ ATPase (SERCA) gene expression.
- SERCA pumps calcium back into the sarcoplasmic reticulum, crucial for muscle relaxation.
Purpose of the Study:
- To investigate if overexpressing the SERCA2 gene improves cardiac calcium handling and contractility.
- To assess the impact of increased SERCA2 expression on systolic and diastolic function.
Main Methods:
- Constructed transgenic mice overexpressing the SERCA2 gene.
- Utilized adenoviruses to overexpress the SERCA2 gene in cardiac myocytes.
- Measured cardiac contractility (dP/dt max, dpP/dt min) in vivo.
- Assessed calcium transients and cell shortening/relengthening in cultured myocytes.
Main Results:
- Transgenic mice showed significantly enhanced systolic contraction and diastolic relaxation compared to controls.
- Adenovirus-mediated SERCA2 overexpression in cardiac myocytes accelerated calcium transients.
- Increased SERCA2 expression led to faster contractile parameters in cell culture.
Conclusions:
- Enhanced SERCA2 gene expression improves cardiac contractile function.
- Both transgenic models and adenovirus-based gene delivery demonstrate the benefits of SERCA2.
- Targeting SERCA2 expression offers a potential strategy for treating heart failure.
Abstract:
Congestive heart failure presents a significant medical problem and accumulating evidence indicates that slow relaxation during diastole maybe at least in part be medlated by decreased expression of the gene coding for the Ca2+ ATPase of the sarcoplasmic reticulum (SR). In order to determine if increased expression of the SR Ca2+ ATPase gene leads to alterations in calcium transients and in contractile behavior we constructed transgenic mice overexpressing the SERCA2 gene. Measuring dP/dt(max) and dpPdt(min) with a 2 French Milar catheter we found a significant Increase in systolic contraction and diastolic relaxation in transgene positive versus transgene negative mice. In addition we constructed adenoviruses overexpressing the gene coding for the Ca2+ ATPase of the sarcoplasmic reticulum. Infacting cardiac myocytes with the adenovirus expressing this transgene led to an accelerated calcium transient. Determining cell shortening and relengthening with a edge detection method indicated that increased expression of the SERCA2 transgene mediated by adenovirus Infection accelerated contractile parameters. In summary increased expression of the SERCA2 transgene leads to an enhancement of cardiac contrectile parameters under in vivo conditions in transgenic mice and in myocytes in cell culture using an adenovirus based approach to increase expression of the SERCAX gene.