Matrix metalloproteinase (MMP)-9, but not MMP-2, is involved in the development and progression of C protein-induced myocarditis and subsequent dilated cardiomyopathy.
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 approximately 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.
Matsumoto
Yoh
Y
Department of Molecular Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Musashidai 2-6, Fuchu, Tokyo 183-8526, Japan. matyoh@tmin.ac.jp
Park
Il-Kwon
IK
Kohyama
Kuniko
K
D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D002352:Carrier Proteins / Q000633:toxicity*; D018450:Disease Progression; D005260:Female; D018836:Inflammation Mediators / Q000502:physiology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000502:physiology; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000502:physiology*; D061965:Matrix Metalloproteinase Inhibitors; D009205:Myocarditis / Q000188:drug therapy / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D011480:Protease Inhibitors / Q000627:therapeutic use; D051381:Rats; D011917:Rats, Inbred Lew; D000099163:Myosin Binding Protein C
D002352:Carrier Proteins; D018836:Inflammation Mediators; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D000099163:Myosin Binding Protein C