Doxycycline Attenuates Isoproterenol-Induced Myocardial Fibrosis and Matrix Metalloproteinase Activity in Rats
Doxycycline Attenuates Isoproterenol-Induced Myocardial Fibrosis and Matrix Metalloproteinase Activity in Rats
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DOI：
10.1248/bpb.32.1678
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发表时间：
2009-10-01
影响因子：
2
通讯作者：
Higuchi, Seiichi
中科院分区：
文献类型：
--
作者：
Hori, Yasutomo;Kunihiro, Shoh-ichi;Higuchi, Seiichi
我们的目的是研究基质金属蛋白酶(MMPI)抑制剂多西环素对β-激动剂诱导的心肌纤维化和基质金属蛋白酶表达的影响。24只大鼠随机分为3组：对照组(CTL；n=8)、异丙肾上腺素(ISO；n=8)和异丙肾上腺素+多西环素(ISO+DOX；n=8)。ISO组和ISO+DOX组大鼠给予L异丙肾上腺素(2.0 mg/kg/d)连续14d，对照组给予赋形剂。另外，ISO+DOX大鼠皮下注射多西环素(25 mg/kg/d)14d，而CTL和ISO大鼠皮下注射生理盐水。通过组织病理学分析评价心肌纤维化程度。用免疫印迹和酶谱方法检测基质金属蛋白酶-2和-9的表达。与对照组相比，ISO组的心肌横截面积和纤维化面积显著增加，而ISO+DOX组的心肌横截面积和纤维化面积明显减轻。ISO组的MMP2活性也显著升高，而ISO+DOX组的MMP2活性降低。同样，免疫印迹显示，在ISO组中，MMP-2和-9的水平显著增加，而在ISO+DOX组中的水平降低。我们的结果提示，MMPs的表达增强在β-激动剂信号通路促进心肌纤维化中起着显著的作用，而基质金属蛋白酶抑制物可能减轻心肌纤维化。
Our objective was to investigate the effects of doxycycline, a matrix metalloproteinase (MMP) inhibitor (MMPi) on beta-agonist-induced myocardial fibrosis and MMP expression. Twenty-four Wistar-Kyoto rats were divided into 3 groups: control (CTL; n=8), isoproterenol (ISO; n=8), and isoproterenol with doxycycline (ISO+DOX; n=8). ISO and ISO+DOX rats received L-isoproterenol (2.0 mg/kg/d) for 14 d, whereas the CTL group received vehicle. In addition, ISO+DOX rats received a subcutaneous injection of doxycycline (25 mg/kg/d) for 14 d, whereas CTL and ISO rats were injected with saline. Cardiac fibrosis was evaluated via histopathological analysis. MMP-2 and -9 were analyzed by Western blotting and zymography. Compared to the control, the myocardial cross-sectional area and areas of fibrosis were increased significantly in the ISO group, but were attenuated in the ISO+DOX group. MMP-2 activity also increased significantly in the ISO group, but decreased in the ISO+DOX group. Similarly, immunoblotting showed significant increase in MMP-2 and -9 levels in the ISO group, and decreased levels in the ISO+DOX group. Our results suggest that the enhanced expression of MMPs plays a prominent role in promoting myocardial fibrosis in beta-agonist signaling pathway, and that MMP-inhibiting compounds may attenuate myocardial fibrosis.