title: The dynamic role of cardiac myosin binding protein-C during ischemia.
abstract: Cardiac myosin binding protein C (cMyBP-C) is a myofibrillar protein important for normal myocardial contractility and stability. In mutated form it can cause cardiomyopathy and heart failure. cMyBP-C appears to have separate regions for different functions. Three phosphorylation sites near the N terminus modulate contractility by their effect on both the kinetics of contraction and the binding site of the N-terminus. The C terminal region binds to myosin rods and stabilizes thick filament structure. The aim of the study reported here was to test whether cMyBPC is important in producing the structural and functional changes that result from ischemia/reperfusion. In this study the sequential changes in cMyBP-C, contractility, and thick filament structure following dephosphorylation of cMyBP-C associated with ischemia and reperfusion have been studied in biopsied specimens from chronically instrumented dogs. One and two dimensional electrophoresis, electron microscopy and immunocytochemistry with multiple antibodies generated against different domains in cMyBP-C have been used to follow structural changes in cMyBP-C. Ischemia produced dephosphorylation of cMyBP-C. Subsequent reperfusion released the dephosphorylated cMyBP-C from myofibrils and activated proteolysis of the cytoplasmic cMyBP-C. This in turn leads to increased vulnerability of cMyBP-C to proteolysis and increased degradation of thick filaments. The state of cMyBP-C appears to be closely related to phosphorylation and dephosphorylation of serine 282. In the absence of the stabilizing action of cMyBP-C either as a consequence of genetic mutation or dephosphorylation, premature degradation of thick filaments occurs and is accompanied by persistent contractile dysfunction.
authors.affiliation: Feinberg Cardiovascular Research Institute, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Decker
authors.forename: Sakie
authors.initials: S
authors.lastname: Nakamura
authors.forename: Marlene L
authors.initials: ML
authors.lastname: Decker
authors.forename: Mareike
authors.initials: M
authors.lastname: Sausamuta
authors.forename: Sammy
authors.initials: S
authors.lastname: Sinno
authors.forename: Kathleen
authors.initials: K
authors.lastname: Harris
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Klocke
authors.forename: Irina
authors.initials: I
authors.lastname: Kulikovskaya
authors.forename: Saul
authors.initials: S
authors.lastname: Winegrad
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D004285:Dogs; D005260:Female; D006321:Heart / Q000503:physiopathology; D006439:Hemodynamics; D008297:Male; D009200:Myocardial Contraction; D017202:Myocardial Ischemia / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009210:Myofibrils / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport; D059748:Proteolysis; D015424:Reperfusion; D000099163:Myosin Binding Protein C
chemical_list: D002352:Carrier Proteins; D000099163:Myosin Binding Protein C