Fig. (2).

Disrupted Ca²⁺ homeostasis in failing cardiomyocytes and therapeutic targeting of SERCA2a. A: Representative confocal line-scan images (left) show that Ca²⁺ release is de-synchronized across failing cells, resulting in smaller and slower Ca²⁺ transients (centre panel, magnified in inset at right). Unpublished data are from a rat model of heart failure following myocardial infarction and sham-operated controls (fluo-4 AM loading). Smaller transients additionally result from declining SR content due to reduced SERCA2a activity. B: SERCA2a activity may be therapeutically increased in heart failure by gene therapy-mediated overexpression or pharmacological stimulation. Phospholamban (PLB)-dependent inhibition of SERCA could be relieved by increasing PLB phosphorylation by: 1) elevating cAMP levels (stimulating β-adrenergic signaling or preventing cAMP breakdown by phosphodiesterases (PDEs)), or 2) preventing PLB dephosphorylation by inhibiting protein phosphatase 1 (PP1), or increasing activity of inhibitor 1 (I-1). Alternatively, competitive inhibition of PLB could be employed.