Nakano Yukiko, Niida Shumpei, Dote Keigo, Takenaka Sou, Hirao Hidekazu, Miura Fumiharu, Ishida Mari, Shingu Tetsuji, Sueda Taijiro, Yoshizumi Masao, Chayama Kazuaki
Department of Medicine and Molecular Science, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, Japan.
J Am Coll Cardiol. 2004 Mar 3;43(5):818-25. doi: 10.1016/j.jacc.2003.08.060.
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).
Matrix metalloproteinases, a family of proteolytic enzymes and TIMPs, regulate the extracellular matrix turnover in cardiac tissue.
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.
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.
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.
本研究旨在确定基质金属蛋白酶（MMPs）-1、-2和-9以及金属蛋白酶组织抑制剂（TIMP）-1与心房颤动（AF）期间心房结构重塑之间的关系。
基质金属蛋白酶是一类蛋白水解酶家族，与TIMP共同调节心脏组织中的细胞外基质周转。
从25例无AF病史（窦性心律[RSR]）的患者和13例接受心脏手术的AF患者（阵发性AF：6例，慢性AF：7例）获取组织样本。我们对MMP-1、-2和-9进行了蛋白质印迹分析，并通过实时聚合酶链反应和酶联免疫吸附测定法定量分析了MMP-9和TIMP-1的表达。通过原位酶谱分析和免疫组织化学研究MMP-9的定位。
与RSR组相比，AF组中MMP-9的活性形式显著增加（p<0.05），但两组间MMP-9潜在形式的蛋白水平以及MMP-1和MMP-2的活性和潜在形式无差异。我们还证明，对于信使核糖核酸（mRNA）（AF：RSR；1：1.5）和蛋白水平（AF：RSR；3.9±1.3：1.5±0.4 ng/mg心房），AF组心房中MMP-9的表达比RSR组显著增加。PAF组中MMP-9的表达水平也高于RSR组，然而，两组左心房直径相似。明胶酶活性与左心房直径呈正相关（p<0.05，R=0.766）。AF组中单核细胞趋化蛋白-1的mRNA相对表达高于RSR组。免疫组织化学分析显示，MMP-9分布于心房血管周围区域和心外膜下。
我们明确表明，颤动心房组织中MMP-9的表达增加，这可能导致了AF期间的心房结构重塑和心房扩张。
