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CLINICAL RESEARCH: ELECTROPHYSIOLOGY

Matrix metalloproteinase-9 contributes to human atrial remodeling during atrial fibrillation

Yukiko Nakano, MD^*,*, Shumpei Niida, PhD, Keigo Dote, MD, Sou Takenaka, MD^*, Hidekazu Hirao, MD^*, Fumiharu Miura, MD^*, Mari Ishida, MD^*, Tetsuji Shingu, MD^*, Taijiro Sueda, MD, Masao Yoshizumi, MD^|| and Kazuaki Chayama, MD^*

^* Department of Medicine and Molecular Science, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, Japan
Department of Geriatric Research, National Institute for Longevity Science (NILS), Nagoya, Japan
Department of Cardiology, Hiroshima City Asa Hospital, Hiroshima, Japan
Department of Surgery, Hiroshima Graduate School of Medicine, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, Japan
^|| Department of Cardiovascular Physiology and Medicine, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, Japan

Manuscript received July 2, 2003; revised manuscript received July 28, 2003, accepted August 5, 2003.

^* Reprint requests and correspondence: Dr. Yukiko Nakano, Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
ynakano{at}xj8.so-net.ne.jp

OBJECTIVES: The purpose of this study was to determine the relationship between matrix metalloproteinases (MMPs)-1, -2, and -9, and tissue inhibitors of metalloproteinases (TIMP)-1 and the atrial structural remodeling during atrial fibrillation (AF).

BACKGROUND: Matrix metalloproteinases, a family of proteolytic enzymes and TIMPs, regulate the extracellular matrix turnover in cardiac tissue.

METHODS: Tissue samples were obtained from 25 patients without a history of AF (regular sinus rhythm [RSR]) and 13 patients with AF (paroxysmal AF: 6, chronic AF 7) undergoing cardiac operations. We performed a western blotting analysis of the MMP-1, -2, and -9, and quantitatively analyzed the expression of the MMP-9 and TIMP-1 by real time polymerase chain reaction and ELISA. The localization of the MMP-9 was investigated by in situ zymography and immunohistochemistry.

RESULTS: The active form of the MMP-9 was significantly increased in the AF group in comparison to that in the RSR group (p < 0.05), but there were no differences between the groups in the protein level of the latent form of the MMP-9 and active and latent forms of the MMP-1 and MMP-2. We also demonstrated that the expression of the MMP-9 was significantly more increased in the atria of the AF group than in that of the RSR group for both the messenger ribonucleic acid (mRNA) (AF: RSR; 1: 1.5) and protein levels (AF: RSR; 3.9 ± 1.3 : 1.5 ± 0.4 ng/mg atrium). The expression level of the MMP-9 was also higher in the PAF group than in the RSR group, however, the diameter of the left atrium was similar in both groups. The gelatinase activity and left atrium diameter were positively correlated (p < 0.05, R = 0.766). The relative expression of the mRNA for the monocyte chemoattractant protein-1 was higher in the AF group than in the RSR group. Immunohistochemical analysis revealed that the MMP-9 was distributed within the perivascular area and under the epicardium of the atria.

CONCLUSIONS: We clearly showed that the expression of the MMP-9 increased in fibrillating atrial tissue, which may have contributed to the atrial structural remodeling and atrial dilatation during AF.

Abbreviations and Acronyms   AF = atrial fibrillation   ADAM = A Disintegrin And Metalloproteinase   MCP-1 = monocyte chemoattractant protein-1   MMPs = matrix metalloproteinases   PAF = paroxysmal AF   RSR = regular sinus rhythm   RT-PCR = reverse transcription-polymerase chain reaction   TIMPs = tissue inhibitors of metalloproteinases

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