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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

View larger version (20K): [in a new window]   Figure 1 Results of the measurement of the matrix metalloproteinase (MMP)-1, -2, and -9 using the Western blotting analysis. The active form of MMP-9 (88 kDa) significantly increased in the atrial fibrillation (AF) group in comparison to that in the regular sinus rhythm (RSR) group (p < 0.05), but there was no difference in the protein level of the latent form of MMP-9 (92 kDa) (top panel). No difference existed in the protein level of the active and latent forms of the MMP-1 (middle panel) and MMP-2 (bottom panel) between the two groups. Closed bars = AF group; open bars = RSR group. *p < 0.05, AF vs. RSR.

View larger version (21K): [in a new window]   Figure 2 Expression level of the MMP-9 protein and tissue inhibitors of metalloproteinase (TIMP)-1 protein by enzyme-linked immunosorbent assay. (A) The expression level of the MMP-9 protein was also higher in the AF group (closed bar) than in the RSR group (open bar) (p < 0.05), and the TIMP-1 protein showed a tendency to rise in the AF patients as compared to that in the RSR patients (p < 0.1). (B) Comparison of the expression of the MMP-9 protein among the three groups. The expression level of MMP-9 was higher not only in the CAF group, but also in the paroxysmal atrial fibrillation (Paf) group, than that in the RSR group. Closed bars = AF group; open bars = RSR group. *p < 0.05, AF vs. RSR. Abbreviations as in Figure 1.

View larger version (22K): [in a new window]   Figure 3 Relative expression of messenger ribonucleic acid (mRNA) from MMP-9, TIMP-1, monocyte chemoattractant protein (MCP)-1, and tumor necrosis factor (TNF-). (A) The relative expression of mRNA from MMP-9 was higher in the AF group than in the RSR group. (B) The relative expression of mRNA from MCP-1 was higher in the AF group than in the RSR group and that of the TNF- was similar in the two groups. Closed bars = AF group; open bars = RSR group. *p < 0.05, AF vs. RSR. Abbreviations as in Figure 1

View larger version (112K): [in a new window]   Figure 4 Hematoxylin-eosin staining and in situ zymography in atria with RSR and AF. Hematoxylin-eosin staining showed that the cell layer under the epicardium of the atrium was thicker with AF (A) than with RSR (B). In situ zymography showed that the activity of gelatinase, represented as unstained spots from the Biebrich scarlet in the FIZ-GN films, was higher in patients with AF (C) than in those with RSR (D). The activity was completely blocked by an MMP inhibitor, which presented as unstained spots in the FIZ-GN films (E) and which disappeared in the FIZ-GI films (F). Original magnification: x200. Abbreviations as in Figure 1.

View larger version (15K): [in a new window]   Figure 5 Relationship between the gelatinase activity and left atrial (LA) diameter. The level of gelatinase activity was positively correlated to the left atrial diameter. (p < 0.05, R = 0.766).

View larger version (121K): [in a new window]   Figure 6 Immunohistochemical analysis of the atria. Immunohistochemical analysis showed that in atria with AF, the MMP-9 exists mainly in the perivascular region (A), under the epicardium (B), and sporadically in the interstitium of cardiomyocites. The staining of the MMP-9 appeared as fibers in the enlarged view (C). In the same region, collagen fibers are stained blue with Masson trichrome (D). Original magnification: A, B x200 and C, D x400. Abbreviations as in Figure 1.

View larger version (131K): [in a new window]   Figure 7 Double staining of the matrix metalloproteinases (MMP)-9 and CD11b in the atria. The double staining of the MMP-9 and CD11b revealed that the distribution of the MMP-9 was not always coincident with that of the CD11b. Original magnification: upper panel x200; lower panel x400.