A recombinant antibody increases cardiac contractility by mimicking phospholamban phosphorylation.
Many cardiovascular disease states end in progressive heart failure. Changes in intracellular calcium handling, including a reduced activity of the sarcoplasmic reticulum calcium pump (SERCA), contribute to this contractile dysfunction. As the regulatory protein phospholamban can inhibit the calcium pump, we evaluated it as a potential target to improve cardiac function. In this study, we describe a recombinant antibody-based protein (PLN-Ab) that binds to the cytoplasmic domain of phospholamban. Fluorescence resonance energy transfer (FRET) studies suggest that PLN-Ab mimics the effects of phospholamban phosphorylation. PLN-Ab accelerated the decay of the calcium transient when expressed in neonatal rat and adult mouse ventricular cardiac myocytes. In addition, direct injection of adenovirus encoding PLN-Ab into the diabetic mouse heart enhanced contractility when measured in vivo by echocardiography and in ex vivo Langendorff perfused hearts. The PLN-Ab provides a novel therapeutic approach to improving contractility through in vivo expression of an antibody inside cardiac myocytes.
Meyer
Markus
M
Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0618, USA.
Belke
Darrell D
DD
Trost
Susanne U
SU
Swanson
Eric
E
Dieterle
Thomas
T
Scott
Brian
B
Cary
Stephen P
SP
Ho
Peter
P
Bluhm
Wolfgang F
WF
McDonough
Patrick M
PM
Silverman
Gregg J
GJ
Dillmann
Wolfgang H
WH
D000595:Amino Acid Sequence; D000818:Animals; D000918:Antibody Specificity; D001483:Base Sequence; D020013:Calcium Signaling / Q000187:drug effects*; D002135:Calcium-Binding Proteins / Q000737:chemistry*; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002316:Cardiotonic Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line / Q000187:drug effects; D002645:Chickens; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D031541:Fluorescence Resonance Energy Transfer; D015316:Genetic Therapy; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000628:therapy*; D006352:Heart Ventricles / Q000166:cytology; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D007668:Kidney; D051379:Mice; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology; D014463:Ultrasonography; D000099211:Phospholamban
D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D002316:Cardiotonic Agents; D007136:Immunoglobulins; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D000099211:Phospholamban; C016512:IgY