Heterogeneous effects of tissue inhibitors of matrix metalloproteinases on cardiac fibroblasts
Heterogeneous effects of tissue inhibitors of matrix metalloproteinases on cardiac fibroblasts
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DOI：
10.1152/ajpheart.00402.2004
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发表时间：
2005-02-01
影响因子：
4.8
通讯作者：
Mann, DL
中科院分区：
文献类型：
--
作者：
Lovelock, JD;Baker, AH;Mann, DL
基质金属蛋白酶(MMPs)与其天然抑制物--金属蛋白酶组织抑制物(TIMPs)之间的平衡在心脏重构中起着关键作用。尽管许多研究已经确定了基质金属蛋白酶在心脏中的病理生理作用，但对基质金属蛋白酶在心脏中的作用知之甚少。为了阐明TIMP在心脏中的作用，我们检测了腺病毒介导的TIMP-1、-2、-3和-4在心脏成纤维细胞中过表达的影响。用含有人重组TIMP的重组腺病毒载体(AdTIMP-1、-2、-3和-4)感染心脏成纤维细胞，可显著增加(P<；0.0001)溴脱氧尿苷(BrdU)的掺入。同样，用AdTIMP-1、-2、-3和-4条件培养液处理心脏成纤维细胞后，BrdU的掺入增加了1.2倍(P<；0.0001)，但这一作用可被抗TIMP-1、-2、-3和-4抗体阻断。TIMPs的作用不能通过RS-130830(一种广泛的基质金属蛋白酶抑制剂)来模拟，这表明TIMPs的作用与其抑制MMPs的能力无关。感染AdTIMP-1、-2、-3和-4后，α-平滑肌肌动蛋白染色显著增加，与TIMP诱导的肌成纤维细胞表型分化一致。最后，AdTIMP-2感染导致胶原合成显著增加，而AdTIMP-3感染导致成纤维细胞凋亡显著增加。TIMP对体外培养的心脏成纤维细胞既有重叠作用，也有不同作用。TIMPs刺激成纤维细胞增殖和向肌成纤维细胞表型分化的观察结果表明，TIMPs可能在心脏组织修复中发挥重要作用，而不仅仅是作为基质金属蛋白酶抑制剂的传统作用。
The balance between matrix metalloproteinases ( MMPs) and their natural inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), plays a critical role in cardiac remodeling. Although a number of studies have characterized the pathophysiological role of MMPs in the heart, very little is known with respect to the role of TIMPs in the heart. To delineate the role of TIMPs in the heart we examined the effects of adenovirus-mediated overexpression of TIMP-1, - 2, - 3, and - 4 in cardiac fibroblasts. Infection of cardiac fibroblasts with adenoviral constructs containing human recombinant TIMP (AdTIMP-1, - 2, - 3, and - 4) provoked a significant ( P < 0.0001) 1.3-fold in increase in bromodeoxyuridine ( BrdU) incorporation. Similarly, treatment of cardiac fibroblasts with AdTIMP-1-, - 2-, - 3-, and - 4-conditioned medium led to a 1.2-fold increase in BrdU incorporation ( P < 0.0001) that was abolished by pretreatment with anti-TIMP-1, - 2, - 3, and - 4 antibodies. The effects of TIMPs were not mimicked by treating the cells with RS-130830, a broad-based MMP inhibitor, suggesting that the effects of TIMPs were independent of their ability to inhibit MMPs. Infection with AdTIMP- 1, - 2, - 3, and - 4 led to a significant increase in alpha-smooth muscle actin staining, consistent with TIMP-induced phenotypic differentiation into myofibroblasts. Finally, infection with AdTIMP- 2 resulted in a significant increase in collagen synthesis, whereas infection with AdTIMP- 3 resulted in a significant increase in fibroblast apoptosis. TIMPs exert overlapping as well as diverse effects on isolated cardiac fibroblasts. The observation that TIMPs stimulate fibroblast proliferation as well as phenotypic differentiation into myofibroblasts suggests that TIMPs may play an important role in tissue repair in the heart that extends beyond their traditional role as MMP inhibitors.