Author:

Keywords:

Animals, Ca(2+)-Transporting ATPase, Calcium, Calcium-Binding Proteins, Cardiomegaly, Comparative Study, Crosses, Genetic, Heart Failure, Congestive, Ion Transport, Longevity, Mice, Mice, Knockout, Physical Conditioning, Animal, Research Support, Non-U.S. Gov't, Sarcoplasmic Reticulum, Stress, Substrate Specificity, Science & Technology, Life Sciences & Biomedicine, Cardiac & Cardiovascular Systems, Cell Biology, Cardiovascular System & Cardiology, sarcoplasmic reticulum Ca2+-ATPase (SERCA), phospholamban, cardiac hypertrophy and dysfunction, calcium cycling, beta-adrenergic stimulation, gene-targeted mice, SARCOPLASMIC-RETICULUM CA2+-ATPASE, HEART-FAILURE, DILATED CARDIOMYOPATHY, GENE-TRANSFER, MURINE HEART, PHOSPHOLAMBAN, CONTRACTILITY, ISOFORMS, ATPASE, OVEREXPRESSION, Calcium-Transporting ATPases, Heart Failure, Sarcoplasmic Reticulum Calcium-Transporting ATPases, Stress, Physiological, 1102 Cardiorespiratory Medicine and Haematology, 1116 Medical Physiology, Cardiovascular System & Hematology, 3101 Biochemistry and cell biology, 3201 Cardiovascular medicine and haematology, 3208 Medical physiology

Abstract:

Abnormal Ca(2+) cycling in the failing heart might be corrected by enhancing the activity of the cardiac Ca(2+) pump, the sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a (SERCA2a) isoform. This can be obtained by increasing the pump's affinity for Ca(2+) by suppressing phospholamban (PLB) activity, the in vivo inhibitor of SERCA2a. In SKO mice, gene-targeted replacement of SERCA2a by SERCA2b, a pump with a higher Ca(2+) affinity, results in cardiac hypertrophy and dysfunction. The stronger PLB inhibition on cardiac morphology and performance observed in SKO was investigated here in DKO mice, which were obtained by crossing SKO with PLB(-/-) mice. The affinity for Ca(2+) of SERCA2 was found to be further increased in these DKO mice. Relative to wild-type and SKO mice, DKO mice were much less spontaneously active and showed a reduced life span. The DKO mice also displayed a severe cardiac phenotype characterized by a more pronounced concentric hypertrophy, diastolic dysfunction and increased ventricular stiffness. Strikingly, beta-adrenergic or forced exercise stress induced acute heart failure and death in DKO mice. Therefore, the increased PLB inhibition represents a compensation for the imposed high Ca(2+)-affinity of SERCA2b in the SKO heart. Limiting SERCA2's affinity for Ca(2+) is physiologically important for normal cardiac function. An improved Ca(2+) transport in the sarcoplasmic reticulum may correct Ca(2+) mishandling in heart failure, but a SERCA pump with a much higher Ca(2+) affinity may be detrimental.