Abstract
We recently reported that mice deficient in the programmed cell death-1 (PD-1) immunoinhibitory coreceptor develop autoimmune dilated cardiomyopathy (DCM), with production of high-titer autoantibodies against a heart-specific, 30-kDa protein. In this study, we purified the 30-kDa protein from heart extract and identified it as cardiac troponin I (cTnI), encoded by a gene in which mutations can cause familial hypertrophic cardiomyopathy (HCM). Administration of monoclonal antibodies to cTnI induced dilatation and dysfunction of hearts in wild-type mice. Monoclonal antibodies to cTnI stained the surface of cardiomyocytes and augmented the voltage-dependent L-type Ca2+ current of normal cardiomyocytes. These findings suggest that antibodies to cTnI induce heart dysfunction and dilatation by chronic stimulation of Ca2+ influx in cardiomyocytes.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal / administration & dosage
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Antigens, CD
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Antigens, Surface / genetics
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Antigens, Surface / immunology*
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Apoptosis Regulatory Proteins
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Autoantibodies / metabolism*
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Base Sequence
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Calcium Signaling
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Cardiomyopathy, Dilated / etiology*
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Cardiomyopathy, Dilated / genetics
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Cardiomyopathy, Dilated / immunology*
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Cardiomyopathy, Dilated / metabolism
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DNA, Complementary / genetics
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Humans
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Mice
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Mice, Inbred A
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Mice, Inbred BALB C
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Mice, Knockout
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Mice, Nude
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Myocytes, Cardiac / immunology
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Myocytes, Cardiac / metabolism
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Programmed Cell Death 1 Receptor
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Rats
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Rats, Wistar
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Troponin I / immunology*
Substances
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Antibodies, Monoclonal
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Antigens, CD
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Antigens, Surface
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Apoptosis Regulatory Proteins
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Autoantibodies
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DNA, Complementary
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PDCD1 protein, human
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Pdcd1 protein, mouse
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Programmed Cell Death 1 Receptor
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Troponin I