Abstract
Loss of contractility is a common feature in heart failure. Sarcoplasmic Reticulum (SR) calcium cycling defect is a major mechanism underlying contractile dysfunction. Phospholamban (PLB) mediated regulation of SERCA activity in normal and failing heart plays an important role in SR calcium cycling. Recently, we discovered a novel isoform of protein phosphatase 2C family (PP2Ce) which is specifically targeted on ER membrane. Northern-blot showed that PP2Ce is highly expressed in heart and other tissue. Expression of PP2Ce in neonatal cardiomyocytes significantly repressed the PLB phosphorylation at the Thr-17 site without remarkable effect on Ser-16 site, which indicating its potent and very specific activity towards the Thr-17 site instead of the Ser-16 site of PLB in cardiomyocytes. By using an inducible a-MHC-in-PP2Ce construct and the Tet-expresser transgenic line, we developed a cardiac specific PP2Ce transgenic mice. PP2Ce expression was remarkably higher in transgenic hearts compared with control, accompanying with the increase in expression of phosphor-CaMKII. There were no significant difference in the cardiac function at basal based on Echocardiography measurements. Expression of PP2Ce markedly delayed the decay of calcium transients with the administration isoproterenol in isolated adult cardiomyocytes and blunted positive inotropic response in transgenic mice heart. In response to ISO treatment, PLB phosphorylation at the Thr-17 site were significantly suppressed in PP2Ce cardaiomyocytes and hearts, while there is no much change at Ser-16 site compared with controls. Our results suggested that PP2Ce may be a novel component of the PLB/SR calcium regulatory machinery involved in cardiac contractile regulation under physiological and pathological conditions and offer new insights to cardiac contractile regulation and failure. This research has received full or partial funding support from the American Heart Association, AHA National Center.
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