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Matrix Metalloproteinase (MMP)-9, but Not MMP-2, Is Involved in the Development and Progression of C Protein-Induced Myocarditis and Subsequent Dilated Cardiomyopathy¹

Department of Molecular Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan

Repeated or continuous inflammation of the heart is one of the initiation factors for dilated cardiomyopathy (DCM). In previous studies, we established a DCM animal model by immunizing rats with cardiac C protein. In the present study, we analyze the role of matrix metalloproteinases (MMPs) in experimental autoimmune carditis (EAC) and subsequent DCM to elucidate the pathomechanisms of this disease. In this model, inflammation begins 9 days after immunization. At that time, MMP activities were detected by in situ zymography. Real-time PCR analysis revealed continuous up-regulation of MMP-2 mRNA from 2 wk and thereafter. MMP-9 mRNA, however, had only a transient increase at 2 wk. Double staining with in situ zymography and cell markers demonstrated that gelatinase (MMP-2 and MMP-9)-expressing cells are infiltrating macrophages during the early stage and cardiomyocytes at later stages. Minocycline, which inhibits MMP-9 activities more strongly than MMP-2, significantly suppressed EAC, but an MMP-2-specific inhibitor, TISAM, did not affect the course of the disease. Furthermore, immunohistochemical examination revealed that minocycline treatment suppressed T cell and macrophage infiltration strongly, whereas TISAM did not. These findings indicate that MMP-9, but not MMP-2, is involved in the pathogenesis of the acute phase of EAC, and further suggest that MMP-9 inhibitors, minocycline and its derivatives, may be useful therapies for EAC and DCM.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by Health and Labour Sciences Research Grants for Research on Psychiatric and Neurological Diseases from the Ministry of Health and Labour, and by Grants-in-Aid from the Ministry of Education and Science, Japan. Y.M. was also supported by the Welfare and Health Fund of the Tokyo Metropolitan Government.

² Address correspondence and reprint requests to Dr. Yoh Matsumoto, Department of Molecular Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Musashidai 2-6, Fuchu, Tokyo 183-8526, Japan. E-mail address: matyoh{at}tmin.ac.jp

³ Abbreviations used in this paper: DCM, dilated cardiomyopathy; CC2, cardiac C protein fragment 2; EAC, experimental autoimmune carditis; FIZ, film in situ zymography; ISZ, in situ zymography; MMP, matrix metalloproteinase; PI, postimmunization.