Phospholamban ablation in hearts expressing the high affinity SERCA2b isoform normalizes global Ca2+ homeostasis but not Ca2+-dependent hypertrophic signaling.

Cardiomyocytes from failing hearts exhibit reduced levels of the sarcoplasmic reticulum (SR) Ca²⁺-ATPase (SERCA) and/or increased activity of the endogenous SERCA inhibitor phospholamban. The resulting reduction in the Ca²⁺ affinity of SERCA impairs SR Ca²⁺ cycling in this condition. We have previously investigated the physiological impact of increasing the Ca²⁺ affinity of SERCA by substituting SERCA2a with the higher affinity SERCA2b pump. When phospholamban was also ablated, these double knockouts (DKO) exhibited a dramatic reduction in total SERCA levels, severe hypertrophy, and diastolic dysfunction. We presently examined the role of cardiomyocyte Ca²⁺ homeostasis in both functional and structural remodeling in these hearts. Despite the low SERCA levels in DKO, we observed near-normal Ca²⁺ homeostasis with rapid Ca²⁺ reuptake even at high Ca²⁺ loads and stimulation frequencies. Well-preserved global Ca²⁺ homeostasis in DKO was paradoxically associated with marked activation of the Ca²⁺- dependent nuclear factor of activated T-cell-calcineurin pathway known to trigger hypertrophy. No activation of the MAP kinase signaling pathway was detected. These findings suggest that local changes in Ca²⁺ homeostasis may play an important signaling role in DKO, perhaps due to reduced microdomain Ca²⁺ buffering by SERCA2b. Furthermore, alterations in global Ca²⁺ homeostasis can also not explain impaired in vivo diastolic function in DKO. Taken together, our results suggest that normalizing global cardiomyocyte Ca²⁺ homeostasis does not necessarily protect against hypertrophy and heart failure development and that excessively increasing SERCA Ca²⁺ affinity may be detrimenta. [ABSTRACT FROM AUTHOR]