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Overexpression of TNNI3K, a cardiac-specific MAP kinase, promotes P19CL6-derived cardiac myogenesis and prevents myocardial infarction-induced injury

Departments of ¹Pharmacology and Molecular Therapeutics, ²Immunogenesis, ³Tumor Genetics and Biology, and ⁴Immunology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; ⁵Molecular Medical Center for Cardiovascular Diseases, Cardiovascular Institute and Fuwai Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing; ⁶The 2^nd Hospital and Institute of Cardiovascular Disease Research Affiliated to Nanchang University, Donghu, Nanchang, People's Republic of China; ⁷Department of Internal Medicine, Sendai Shakaihoken Hospital, Sendai; ⁸Departments of Cardiovascular Medicine and Clinical Bioinformatics, University of Tokyo Graduate School of Medical Sciences, Tokyo; and ⁹Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medical Sciences, Chiba, Japan

Submitted 11 March 2008 ; accepted in final form 5 June 2008

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 -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.

cardiomyogenesis; apoptosis