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Identification of biochemical adaptations in hyper- or hypocontractile hearts from phospholamban mutant mice by expression proteomics

2004; National Academy of Sciences; Volume: 101; Issue: 8 Linguagem: Inglês

10.1073/pnas.0308174101

1091-6490

Yan Pan, Thomas Kislinger, Anthony O. Gramolini, Elena Zvaritch, Evangelia G. Kranias, David H. MacLennan, Andrew Emili,

Mass Spectrometry Techniques and Applications

Phospholamban (PLN) is a critical regulator of cardiac contractility through its binding to and regulation of the activity of the sarco(endo)plasmic reticulum Ca 2+ ATPase. To uncover biochemical adaptations associated with extremes of cardiac muscle contractility, we used high-throughput gel-free tandem MS to monitor differences in the relative abundance of membrane proteins in standard microsomal fractions isolated from the hearts of PLN-null mice (PLN-KO) with high contractility and from transgenic mice overexpressing a superinhibitory PLN mutant in a PLN-null background (I40A-KO) with diminished contractility. Significant differential expression was detected for a subset of the 782 proteins identified, including known membrane-associated biomarkers, components of signaling pathways, and previously uninvestigated proteins. Proteins involved in fat and carbohydrate metabolism and proteins linked to G protein-signaling pathways activating protein kinase C were enriched in I40A-KO cardiac muscle, whereas proteins linked to enhanced contractile function were enriched in PLN-KO mutant hearts. These data demonstrate that Ca 2+ dysregulation, leading to elevated or depressed cardiac contractility, induces compensatory biochemical responses.