Regulation of expression of cardiac sarcoplasmic reticulum proteins under pathophysiological conditions
Congestive heart failure presents a significant medical problem and accumulating evidence indicates that slow relaxation during diastole maybe at least in part be mediated 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/dtmax and dpPdtmin 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.
Key wordscongestive heart failure cardiac relaxation calcium ATPase of the sarcoplasmic reticulum transgenic mice adenoviruses gene therapy
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