REGULATION OF EXPRESSION OF CARDIAC SARCOPLASMIC-RETICULUM PROTEINS UNDER PATHOPHYSIOLOGICAL CONDITIONS

Congestive heart failure presents a significant medical problem and ac cumulating evidence indicates that slow relaxation during diastole may be at least in part be mediated by decreased expression of the gene co ding 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 co nstructed transgenic mice overexpressing the SERCA2 gene. Measuring dP /dt(max) and dpPdt(min) With a 2 French h Milar catheter we found a si gnificant Increase in systolic contraction and diastolic relaxation in transgene positive versus transgene negative mice. In addition we con structed adenoviruses overexpressing the gene coding for the Ca2+ ATPa se of the sarcoplasmic reticulum. Infacting cardiac myocytes with the adenovirus expressing this transgene led to an accelerated calcium tra nsient. Determining cell shortening and relengthening with a edge dete ction method indicated that increased expression of the SERCA2 transge ne 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 adenoviru s based approach to increase expression of the SERCAX gene.