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.
- adverse
- animal,
- animals;
- atpases,
- atpases;
- calcium,
- calcium-binding
- calcium-transporting
- cardiomegaly,
- conditioning,
- crosses,
- deficiency/metabolism;
- effects;
- failure,
- genetic;
- genetics
- genetics/metabolism/pathology;
- genetics;
- heart
- ion
- knockout;
- longevity,
- metabolism;
- mice,
- mice;
- physical
- physiological;
- proteins,
- reticulum
- reticulum,
- sarcoplasmic
- specificity,
- stress,
- substrate
- transport,
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