The relative phospholamban and SERCA2 ratio: a critical determinant of myocardial contractility.
Phospholamban is a regulatory phosphoprotein which modulates the active transport of Ca2+ by the cardiac sarcoplasmic reticular Ca(2+)-ATPase enzyme (SERCA2) into the lumen of the sarcoplasmic reticulum. Phospholamban, which is a reversible inhibitor of SERCA2, represses the enzyme's activity, and this inhibition is relieved upon phosphorylation of phospholamban in response to beta-adrenergic stimulation. In this way, phospholamban is an important regulator of SERCA2-mediated myocardial relaxation during diastole. This report centers on the hypothesis that the relative levels of phospholamban: SERCA2 in cardiac muscle plays an important role in the muscle's overall contractility status. This hypothesis was tested by comparing the contractile parameters of: a) murine atrial and ventricular muscles, which differentially express phospholamban, and b) murine wild-type and phospholamban knock-out hearts. These comparisons revealed that atrial muscles, which have a 4.2-fold lower phospholamban: SERCA2 ratio than ventricular muscles, exhibited rates of force development and relaxation of tension, which were three-fold faster that these parameters for ventricular muscles. Similar comparisons were made via analyses of left-ventricular pressure development recorded for isolated, work-performing hearts from wild-type and phospholamban knock-out mice. In these studies, hearts from phospholamban knock-out mice, which were devoid of phospholamban, exhibited enhanced parameters of left-ventricular contractility in comparison to wild-type hearts. These results suggest that the relative phospholamban: SERCA2 ratio is critical in the regulation of myocardial contractility and alterations in this ratio may contribute to the functional deterioration observed during heart failure.
Koss
K L
KL
Dept. of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Ohio 45267-0575, USA.
Grupp
I L
IL
Kranias
E G
EG
D000818:Animals; D000835:Animals, Wild; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006325:Heart Atria; D006352:Heart Ventricles; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000201:enzymology; D012519:Sarcoplasmic Reticulum / Q000201:enzymology*; D014158:Transcription, Genetic; D000099211:Phospholamban
D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D000099211:Phospholamban