Induced overexpression of phospholemman S68E mutant improves cardiac contractility and mortality after ischemia-reperfusion

Phospholemman (PLM), when phosphorylated at Ser68, inhibits car-diac Na/Ca2 exchanger 1 (NCX1) and relieves its inhibition on Na-K-ATPase. We have engineered mice in which expression of the phosphomimetic PLM S68E mutant was induced when dietary doxycycline was removed at 5 wk. At 8–10 wk, compared with noninduced or wild-type hearts, S68E expression in induced hearts was 35–75 % that of endogenous PLM, but protein levels of sarco-(endo)plasmic reticulum Ca2-ATPase, 1- and 2-subunits of Na-K-ATPase, 1c-subunit of L-type Ca2 channel, and phosphorylated ryanodine receptor were unchanged. The NCX1 protein level was increased by47 % but the NCX1 current was depressed by34 % in induced hearts. Isoproterenol had no effect on NCX1 currents but stimulated Na-K-ATPase currents equally in induced and nonin-duced myocytes. At baseline, systolic intracellular Ca2 concentra-tions ([Ca2]i), sarcoplasmic reticulum Ca2 contents, and [Ca2]