Phospholamban phosphorylation during ischemia and reperfusion injury: Mechanisms and functional implications.

MATTIAZZI A., MUNDIÑA-WEILENMANN C., VITTONE L., SAID M., FERRERO P.

Myocardial Ischemia and Preconditioning

Kluwer Academic Publishers

Lugar: Boston, USA; Año: 2002; p. 71 - 81

  Phospholamban phosphorylation during Ischemia and Reperfusion Injury: Mechanisms and Functional Implications Alicia Mattiazzi, Cecilia Mundiña-Weilenmann, Leticia Vittone, Matilde Said and Paola Ferrero Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, 60 y 120, 1900, La Plata, Argentina. Summary: Phospholamban (PLB) is a sarcoplasmic reticulum (SR) protein that in the dephosphorylated state, tonically inhibits the SR Ca2+ pump. Phosphorylation of PLB relieves this inhibition. PLB can be phosphorylated in vivo by cAMP-dependent protein kinase (PKA) at Ser16 and Ca2+-calmodulin –dependent protein kinase (CaMKII) at Thr17. Because the SR dysfunction is an important alteration in ischemia-reperfused hearts, the present paper examines the state of phosphorylation of both PLB residues and their possible functional consequences during ischemia and reperfusion in Langendorff-perfused rat hearts. Ser16 phosphorylation significantly increased by the end of ischemia and decreased towards control values immediately after reperfusion. This increase is dependent on the beta-adrenergic cascade, since it was significantly diminished in hearts from catecholamine-depleted animals and beta-blockade and abolished by the PKA-inhibitor, H-89. Thr17 phosphorylation transiently increased at the beginning of ischemia and at 1 min of reperfusion (R1). The increase in Thr17 phosphorylation is dependent on Ca2+ influx. At the beginning of ischemia it was blunted by nifedipine, whereas at R1 it was not affected by the Ca2+ channel blocker but was significantly diminished by the inhibitor of the reverse mode of the Na+/Ca2+ exchanger, KB-R7943. KN-93, used to specifically inhibit CaMKII, decreased Thr17 phosphorylation and significantly prolonged half relaxation time at R1. Phosphorylation of Thr17 at the onset of reflow may provide the cell a mechanism to cope with Ca2+ overload, transiently favouring recovery of relaxation during early reperfusion.