Key result
Replacing SERCA2a with SERCA2b in mice increases early mortality by ~20% and impairs cardiac contraction.
Why the study?
The requirement of muscle-specific SERCA2a isoform for normal cardiac function and development was unclear.
The muscle-specific SERCA2a isoform is essential for normal cardiac development and the contraction-relaxation cycle, as its replacement by SERCA2b leads to hypertrophy and impaired cardiac function.
Answers are grounded in this paper and cite their sources.
SERCA2a isoform specificity is essential in cardiac muscle; leaves open whether selective modulation offers therapeutic benefit in human HF.
The cardiac sarco(endo)plasmic reticulum Ca(2+)-ATPase gene (ATP2A2) encodes the following two different protein isoforms: SERCA2a (muscle-specific) and SERCA2b (ubiquitous). We have investigated whether this isoform specificity is required for normal cardiac function. Gene targeting in mice successfully disrupted the splicing mechanism responsible for generating the SERCA2a isoform. Homozygous SERCA2a(-/-) mice displayed a complete loss of SERCA2a mRNA and protein resulting in a switch to the SERCA2b isoform. The expression of SERCA2b mRNA and protein in hearts of SERCA2a(-/-) mice corresponded to only 50% of wild-type SERCA2 levels. Cardiac phospholamban mRNA levels were unaltered in SERCA2a(-/-) mice, but total phospholamban protein levels increased 2-fold. The transgenic phenotype was characterized by a approximately 20% increase in embryonic and neonatal mortality (early phenotype), with histopathologic evidence of major cardiac malformations. Adult SERCA2a(-/-) animals (adult phenotype) showed a reduced spontaneous nocturnal activity and developed a mild compensatory concentric cardiac hypertrophy with impaired cardiac contractility and relaxation, but preserved beta-adrenergic response. Ca(2+) uptake levels in SERCA2a(-/-) cardiac homogenates were reduced by approximately 50%. In isolated cells, relaxation and Ca(2+) removal by the SR were significantly reduced. Comparison of our data with those obtained in mice expressing similar cardiac levels of SERCA2a instead of SERCA2b indicate the importance of the muscle-specific SERCA2a isoform for normal cardiac development and for the cardiac contraction-relaxation cycle.
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Heyen et al. (2001) studied Cardiac function and development. SERCA2a gene disruption (SERCA2a(-/-)) vs. Wild-type mice was evaluated on Cardiac function, mortality, and morphology. Replacement of the muscle-specific SERCA2a isoform by SERCA2b in mice caused a ~20% increase in early mortality, mild concentric cardiac hypertrophy, and impaired contraction-relaxation.
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