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(Circulation Research. 2003;92:881.)
© 2003 American Heart Association, Inc.

Cellular Biology

Ca²⁺ Uptake by the Sarcoplasmic Reticulum in Ventricular Myocytes of the SERCA2^b/b Mouse Is Impaired at Higher Ca²⁺ Loads Only

Gudrun Antoons, Mark Ver Heyen, Luc Raeymaekers, Peter Vangheluwe, Frank Wuytack, Karin R. Sipido

From the Laboratories of Experimental Cardiology (G.A., K.R.S.) and Physiology (M.V.H., L.R., P.V., F.W.), University of Leuven, Belgium.

Correspondence to Karin R. Sipido, MD, PhD, Laboratory of Experimental Cardiology, KUL, Campus Gasthuisberg O/N 7th floor, Herestraat 49, B-3000 Leuven, Belgium. E-mail Karin.Sipido{at}med.kuleuven.ac.be

SERCA2a is the cardiac-specific isoform of Ca²⁺-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^b/b), showed only moderate functional impairment, despite a reduction by 40% of the SERCA2 protein levels. We examined in more detail the Ca²⁺ handling in isolated cardiac myocytes from SERCA2^b/b. At 0.25 Hz stimulation, the amplitude of the [Ca²⁺]_i transients, SR Ca²⁺ content, diastolic [Ca²⁺]_i, and density of I_CaL were comparable between WT and SERCA2^b/b. However, the decline of [Ca²⁺]_i was slower (t_1/2 154±7 versus 131±5 ms; P<0.05). Reducing the amplitude of the [Ca²⁺]_i transient (eg, SR depletion), removed the differences in [Ca²⁺]_i decline. In contrast, increasing the Ca²⁺ load revealed pronounced reduction of SR Ca²⁺ uptake at high [Ca²⁺]_i. There was no increase in Na⁺-Ca²⁺ exchange protein or function. Theoretical modeling indicated that in the SERCA2^b/b mouse, the higher Ca²⁺ affinity of SERCA2b partially compensates for the 40% reduction of SERCA expression. The lack of SR depletion in the SERCA2^b/b may also be related to the absence of upregulation of Na⁺-Ca²⁺ exchange. We conclude that for SERCA isoforms with increased affinity for Ca²⁺, a reduced expression level is better tolerated as Ca²⁺ uptake and storage are impaired only at higher Ca²⁺ loads.

Key Words: ventricular myocytes • transgenic mice • sarcoplasmic reticulum Ca²⁺-ATPase • excitation-contraction coupling • Na⁺-Ca²⁺ exchange

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