Ca Uptake by the Sarcoplasmic Reticulum in Ventricular Myocytes of the SERCA2 Mouse Is Impaired at Higher Ca Loads Only

SERCA2a is the cardiac-specific isoform of Ca -ATPase of the sarcoplasmic reticulum (SR). A reduction of SERCA2a has been implicated in the contractile dysfunction of heart failure, and partial knockout of the SERCA2 gene (Atp2a2 / mice) reiterated many of the features of heart failure. Yet, mice with a mutation of Atp2a2, resulting in full suppression of the SERCA2a isoform and expression of the SERCA2b isoform only (SERCA2), showed only moderate functional impairment, despite a reduction by 40% of the SERCA2 protein levels. We examined in more detail the Ca handling in isolated cardiac myocytes from SERCA2. At 0.25 Hz stimulation, the amplitude of the [Ca ]i transients, SR Ca content, diastolic [Ca ]i, and density of ICaL were comparable between WT and SERCA2 . However, the decline of [Ca ]i was slower (t1/2 154 7 versus 131 5 ms; P 0.05). Reducing the amplitude of the [Ca 2 ]i transient (eg, SR depletion), removed the differences in [Ca ]i decline. In contrast, increasing the Ca 2 load revealed pronounced reduction of SR Ca uptake at high [Ca ]i. There was no increase in Na -Ca exchange protein or function. Theoretical modeling indicated that in the SERCA2 mouse, the higher Ca affinity of SERCA2b partially compensates for the 40% reduction of SERCA expression. The lack of SR depletion in the SERCA2 may also be related to the absence of upregulation of Na -Ca exchange. We conclude that for SERCA isoforms with increased affinity for Ca , a reduced expression level is better tolerated as Ca uptake and storage are impaired only at higher Ca loads. (Circ Res. 2003;92:881-887.)