Abstract
TNNI3K is a new cardiac-specific MAP kinase whose gene is localized to 1p31.1 and that belongs to a tyrosine kinase-like branch in the kinase tree of the human genome. In the present study we investigated the role of TNNI3K in the cardiac myogenesis process and in the repair of ischemic injury. Pluripotent P19CL6 cells with or without transfection by pcDNA6-TNNI3K plasmid were used to induce differentiation into beating cardiomyocytes. TNNI3K promoted the differentiation process, judging from the increasing beating mass and increased number of alpha-actinin-positive cells. TNNI3K improved cardiac function by enhancing beating frequency and increasing the contractile force and epinephrine response of spontaneous action potentials without an increase of the single-cell size. TNNI3K suppressed phosphorylation of cardiac troponin I, annexin-V(+) cells, Bax protein, and p38/JNK-mediated apoptosis. Intramyocardial administration of TNNI3K-overexpressing P19CL6 cells in mice with myocardial infarction improved cardiac performance and attenuated ventricular remodeling compared with injection of wild-type P19CL6 cells. In conclusion, our study clearly indicates that TNNI3K promotes cardiomyogenesis, enhances cardiac performance, and protects the myocardium from ischemic injury by suppressing p38/JNK-mediated apoptosis. Therefore, modulation of TNNI3K activity would be a useful therapeutic approach for ischemic cardiac disease.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Actinin / metabolism
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Action Potentials
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Animals
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Annexin A5 / metabolism
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Apoptosis
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Cell Differentiation*
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Cell Line, Tumor
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Cell Proliferation
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Disease Models, Animal
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Embryonal Carcinoma Stem Cells / enzymology*
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Embryonal Carcinoma Stem Cells / pathology
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Embryonal Carcinoma Stem Cells / transplantation
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Epinephrine / metabolism
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Humans
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JNK Mitogen-Activated Protein Kinases / metabolism
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MAP Kinase Kinase Kinases / genetics
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MAP Kinase Kinase Kinases / metabolism*
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Male
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Mice
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Mice, Inbred C57BL
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Molecular Sequence Data
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Muscle Development*
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Myocardial Contraction
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Myocardial Infarction / enzymology
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Myocardial Infarction / pathology
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Myocardial Infarction / physiopathology
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Myocardial Infarction / surgery*
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Myocytes, Cardiac / enzymology*
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Myocytes, Cardiac / pathology
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Myocytes, Cardiac / transplantation
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Phosphorylation
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Pluripotent Stem Cells / enzymology*
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Pluripotent Stem Cells / pathology
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Pluripotent Stem Cells / transplantation
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Protein Serine-Threonine Kinases
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Stem Cell Transplantation
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Transfection
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Troponin I / metabolism
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Ventricular Function, Left
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Ventricular Remodeling
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bcl-2-Associated X Protein / metabolism
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Annexin A5
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Bax protein, mouse
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Troponin I
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bcl-2-Associated X Protein
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Actinin
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Protein Serine-Threonine Kinases
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TNNI3K protein, human
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JNK Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinases
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Epinephrine
Associated data
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GENBANK/AF116826
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GENBANK/NM015978