Identification of biochemical adaptations in hyper- or hypocontractile hearts from phospholamban mutant mice by expression proteomics.
Phospholamban (PLN) is a critical regulator of cardiac contractility through its binding to and regulation of the activity of the sarco(endo)plasmic reticulum Ca2+ 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 Ca2+ dysregulation, leading to elevated or depressed cardiac contractility, induces compensatory biochemical responses.
Banting and Best Department of Medical Research, University of Toronto, Toronto, ON, Canada M5G 1L6.
Yan
Y
Pan
Thomas
T
Kislinger
Anthony O
AO
Gramolini
Elena
E
Zvaritch
Evangelia G
EG
Kranias
David H
DH
MacLennan
Andrew
A
Emili
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D001483:Base Sequence; D002135:Calcium-Binding Proteins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D004798:Enzymes / Q000235:genetics; D020869:Gene Expression Profiling; D005838:Genotype; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008861:Microsomes / Q000378:metabolism; D008969:Molecular Sequence Data; D009200:Myocardial Contraction / Q000235:genetics*; D018995:Myosin Heavy Chains / Q000235:genetics; D011506:Proteins / Q000235:genetics; D000099211:Phospholamban
D009320:Atrial Natriuretic Factor; D002135:Calcium-Binding Proteins; D004798:Enzymes; D018995:Myosin Heavy Chains; D011506:Proteins; D000099211:Phospholamban