摘要
大量研究表明,肿瘤坏死因子α(TNFα)在心肌缺血/再灌注(I/R)损伤中,既能促进心肌损伤,又具有保护心肌的作用,这种看似相互矛盾的作用,系因在心肌I/R的不同时期由不同的信号转导通路所介导。在心肌I/R的急性期,缺血区冠脉血管床的内皮细胞受损,黏附血中巨噬细胞与淋巴细胞可释放大量可溶型TNFα(sTNFα)。高浓度的sTNFα可激活TNF的1型受体(TNFR1)及其下游信号转导通路,引起心肌细胞凋亡。在心肌I/R的重构期或修复期,虽然血中sTNFα的水平高于生理浓度,但血中可溶型TNFR的水平增加可中和sTNFα,阻止其对正常心肌组织的损害。心肌局部缺血可刺激心肌细胞与成纤维细胞合成TNFα,在细胞膜上装配为跨膜型TNFα,激活相邻细胞的2型TNF受体(TNFR2)及其下游信号转导通路,增强心肌细胞钙转运而增强其收缩功能,同时拯救缺血边界区可存活的心肌细胞。心肌局部跨膜型TNFα还能募集间充质干细胞,分泌多种细胞生长因子,改善心功能。TNFα可通过组蛋白去乙酰化酶1(HDAC1)调节核转录因子κB(NF-κB)的转录活性,保护心肌细胞在持续的TNFα作用下得以存活。跨膜型TNFα还可激活心肌中固有的干细胞向心肌细胞分化,修复受损的心肌组织。
Many studies have shown that tumor necrosis factor-or （TNF-a） plays a self-contradictory role in myocardial ischemia/reperfusion （I/R） injury, i. e. , protection and injury. The self-contradictory effect actually takes place in different periods of myocardial I/R mediated by the different signal transduction pathways. Acute I/R damages coronary endothelia in ischemia zone and induces the adherence of macrophages and lymphocytes to release soluble TNF-a （sTNFa）. High levels of sTNF-a activate tumor necrosis factor receptor 1 （TNFR1） and its downstream signal transduction pathways to cause cardiomyo eyte apoptosis. In the remodeling or repairing period of myocardial I/R, althought sTNF-a level is higher than that of physiological condition in plasma, the increased soluble TNFR neutralizes sTNF-a to prevent it from injuring normal myocardial tissue in the remote zone. The local ischemia of myocardium stimulates cardiomyocytes and fibroblasts to synthesize transmembrane TNF-a, which then activates tumor necrosis factor receptor 2 and its downstream transduction pathway in nearby cells. Therefore, calcium transport and contractile function of cardiomyocytes enhanced and survived cardiomyocytes in the border zone are saved. The local transmembrane TNF-ot can recruit mesenchymal stem ceils to release cytokine and growth factors, which improve cardiac function. Transmembrane TNF-a depresses histone deacetylases 1 （HDAC1）. HDAC1 provides a molecular switch for determinin cellular s urvival in the TNF-a pathwayvia modulating NF-KB gene transcription. Transmembrane TNF-a also results in resident cardiac stem cells differentiated toward cardiomyocytes and repair the injured myocardium tissue.
出处
《心脏杂志》
CAS
2014年第3期357-360,365,共5页
Chinese Heart Journal
