Increased expression of plasminogen activator inhibitor-1 in cardiomyocytes contributes to cardiac fibrosis after myocardial infarction
Increased expression of plasminogen activator inhibitor-1 in cardiomyocytes contributes to cardiac fibrosis after myocardial infarction
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DOI：
10.1016/s0002-9440(10)63135-5
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发表时间：
2004-02-01
影响因子：
6
通讯作者：
Yamamoto, K
中科院分区：
文献类型：
--
作者：
Takeshita, K;Hayashi, M;Yamamoto, K
纤溶酶原激活物抑制剂-1（派-1）通过抑制基质金属蛋白酶（MMP-2）的活性在组织纤维化中起重要作用，可能影响左心室功能不全的进展。然而，很少有人知道派-1在心脏重塑过程中的表达。我们使用了小鼠模型的心肌梗死（MI）的冠状动脉结扎，其中左心室重构的进展证实了超声心动图。组织学检查显示，术后4周，All（PMI）心脏的间质和血管周围纤维化进展。与假手术组相比，PMI组小鼠心脏派-1 mRNA和血浆中派-1抗原显著增加。原位杂交结果显示，派-1 mRNA的强信号主要分布于心肌梗死区边缘和纤维病变周围的心肌细胞，而血管周围的单个核细胞（肥大细胞）仅分布于PMI小鼠的心脏。重要的是，与野生型小鼠相比，在派-1缺陷的小鼠中观察到MI后心脏纤维化的发展较少。细胞因子、转化生长因子-β和肿瘤坏死因子-α的mRNA表达在PMI小鼠的心脏中也增加，但在假手术小鼠中没有。这些观察结果表明，心肌细胞和肥大细胞有助于增加派-1的表达，导致在PMI心脏的间质和血管周围纤维化的发展，并在这个过程中可能涉及的区域诱导的细胞因子。
Plasminogen activator inhibitor-1 (PAI-1) plays a critical role in tissue fibrosis by inactivating matrix metalloproteinases, which might effect on the progression of left ventricular dysfunction. However, little has been known about the expression of PAI-1 during cardiac remodeling. We used a mouse model of myocardial infarction (MI) by coronary ligation, in which the progression of left ventricular remodeling was confirmed by echocardiography. Histological examination showed that interstitial and perivascular fibrosis progressed in the post-All (PMI) heart at 4 weeks after the procedure. We observed the dramatic induction of cardiac PAI-1 mRNA and PAI-1 antigen in plasma in the PMI mice, as compared with the shamoperated (sham) mice. In situ hybridization analysis demonstrated that strong signals for PAI-1 mRNA were localized to cardiomyocytes in the boarder of infarct area and around fibrous lesions, and to perivascular mononuclear cells, which seemed to be mast cells, only in hearts of the PMI mice. Importantly, less development of cardiac fibrosis after MI was observed in mice deficient in PAI-1 as compared to wild-type mice. The mRNA expression of cytokines, transforming growth factor-beta, and tumor necrosis factor-alpha, was also increased in hearts of the PMI mice, but not in the sham mice. These observations suggest that cardiomyocytes and mast cells contribute to the increased PAI-1 expression, resulting in the development of interstitial and perivascular fibrosis in the PMI heart, and that the regional induction of cytokines may be involved in this process.