Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Antibody Specificity
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Base Sequence
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Calcium Signaling / drug effects*
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Calcium-Binding Proteins / chemistry*
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Calcium-Transporting ATPases / metabolism
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Cardiotonic Agents / chemistry
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Cardiotonic Agents / pharmacology*
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Cell Line / drug effects
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Chickens
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Diabetes Mellitus, Experimental / metabolism
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Fluorescence Resonance Energy Transfer
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Genetic Therapy*
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Heart Failure / diagnostic imaging
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Heart Failure / therapy*
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Heart Ventricles / cytology
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Humans
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Immunoglobulins / genetics
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Immunoglobulins / immunology
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Immunoglobulins / pharmacology*
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Kidney
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Mice
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Molecular Mimicry
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Molecular Sequence Data
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Myocardial Contraction / drug effects*
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Myocytes, Cardiac / drug effects*
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Myocytes, Cardiac / physiology
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Peptide Fragments / chemistry
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Peptide Fragments / immunology
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Phosphorylation
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Protein Binding
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Protein Structure, Tertiary
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Rats
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / pharmacology
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Ultrasonography
Substances
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Calcium-Binding Proteins
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Cardiotonic Agents
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IgY
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Immunoglobulins
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Peptide Fragments
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Recombinant Fusion Proteins
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phospholamban
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Calcium-Transporting ATPases