| First Author | Wang J | Year | 2014 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 306 |
| Issue | 7 | Pages | H1066-77 |
| PubMed ID | 24486513 | Mgi Jnum | J:279260 |
| Mgi Id | MGI:6359080 | Doi | 10.1152/ajpheart.00861.2013 |
| Citation | Wang J, et al. (2014) Induced overexpression of phospholemman S68E mutant improves cardiac contractility and mortality after ischemia-reperfusion. Am J Physiol Heart Circ Physiol 306(7):H1066-77 |
| abstractText | Phospholemman (PLM), when phosphorylated at Ser(68), inhibits cardiac 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 approximately 35-75% that of endogenous PLM, but protein levels of sarco(endo)plasmic reticulum Ca2+ -ATPase, alpha1- and alpha2-subunits of Na+ -K+ -ATPase, alpha1c-subunit of L-type Ca2+ channel, and phosphorylated ryanodine receptor were unchanged. The NCX1 protein level was increased by approximately 47% but the NCX1 current was depressed by approximately 34% in induced hearts. Isoproterenol had no effect on NCX1 currents but stimulated Na+ -K+ -ATPase currents equally in induced and noninduced myocytes. At baseline, systolic intracellular Ca2+ concentrations ([Ca2+]i), sarcoplasmic reticulum Ca2+ contents, and [Ca(2+)]i transient and contraction amplitudes were similar between induced and noninduced myocytes. Isoproterenol stimulation resulted in much higher systolic [Ca2+]i, sarcoplasmic reticulum Ca2+ content, and [Ca2+]i transient and contraction amplitudes in induced myocytes. Echocardiography and in vivo close-chest catheterization demonstrated similar baseline myocardial function, but isoproterenol induced a significantly higher +dP/dt in induced compared with noninduced hearts. In contrast to the 50% mortality observed in mice constitutively overexpressing the S68E mutant, induced mice had similar survival as wild-type and noninduced mice. After ischemia-reperfusion, despite similar areas at risk and left ventricular infarct sizes, induced mice had significantly higher +dP/dt and -dP/dt and lower perioperative mortality compared with noninduced mice. We propose that phosphorylated PLM may be a novel therapeutic target in ischemic heart disease. |
