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背景:分离整合素金属蛋白酶(ADAMs)可能通过改变细胞表面的基质受体(整合素)、激活生物分子而参与心脏结构的重塑。我们在不同模式的重塑心肌组织中比较了ADAMs、其内源性抑制剂TIMP-3和整合素的表达差异。方法和结果:心肌组织取材于扩张型心肌病(n=20例)、梗阻性肥厚型心肌病(n=5例)和心功能正常的供体(n=7例)。匹配的样本(n=10例)来源于左室辅助装置植入之前和心脏移植时。通过免疫印迹法检测 ADAM10、ADAM12、ADAM15和ADAM17、TIMP-3以及β1D整合素受体、β整合素受体的表达。整合素脱落的测量是通过计算整合素裂解产物和完整整合素的比例而得到。扩张型心肌病中ADAM10、ADAM15表达增高而TIMP-3表达降低。β1D整合素裂解产物比例升高,提示受体脱落。ADAM10、ADAM15表达与裂解产物比例相关。共聚焦显微镜观察到ADAM10与β1D整合素的分布部位一致。ADAM10的表达和室腔扩张、收缩功能不全等临床指标相关。血流动力学改善减少ADAM10和ADAM12的表达,却上调β1D整合素的表达。在梗阻性肥厚型心肌病中,ADAM12和β1D整合素的表达均增加。ADAM17在扩张型心肌病和梗阻性肥厚型心肌病中均见表达上调。结论:ADAMs在人心肌组织的表达差异反映了不同的心肌重塑模式,ADAM10和ADAM15 可能通过引起整合素脱落而减少细胞基质的相互作用参与心脏扩张。因此,以ADAMs为靶标,通过基因或细胞治疗恢复缺乏的TIMP-3,可能阻止扩张型心肌病的进行性心腔扩张。
BACKGROUND: Isolation of integrin metalloproteinases (ADAMs) may participate in the remodeling of heart structure by altering the stromal receptors (integrins) on the cell surface and activating biomolecules. We compared the expression of ADAMs, TIMP-3 and integrin, in different remodeling myocardium. METHODS AND RESULTS: Myocardial tissue was derived from dilated cardiomyopathy (n = 20), obstructive hypertrophic cardiomyopathy (n = 5) and donor with normal cardiac function (n = 7). Matched samples (n = 10) were derived from left ventricular assist devices prior to implantation and at heart transplantation. The expression of ADAM10, ADAM12, ADAM15 and ADAM17, TIMP-3 and β1D integrin receptors, β integrin receptors were detected by immunoblotting. Integrin shedding is measured by calculating the ratio of integrin lysate and intact integrins. Dilated cardiomyopathy ADAM10, ADAM15 increased expression of TIMP-3 decreased. β1D integrin lysate increased the proportion, suggesting that the receptor off. ADAM10, ADAM15 expression and the proportion of cleavage products. Confocal microscopy showed that the distribution of ADAM10 and β1D integrins was consistent. ADAM10 expression and ventricular dilation, systolic dysfunction and other clinical indicators related. Hemodynamic improvement decreased the expression of ADAM10 and ADAM12, but up-regulated the expression of β1D integrin. In obstructive hypertrophic cardiomyopathy, the expression of both ADAM12 and β1D integrins increased. ADAM17 expression in both dilated cardiomyopathy and obstructive hypertrophic cardiomyopathy were upregulated. CONCLUSION: The differences in the expression of ADAMs in human myocardium reflect different modes of myocardial remodeling. ADAM10 and ADAM15 may participate in cardiac dilatation by reducing the interaction of cell matrix with the release of integrin. Thus, targeting ADAMs as targets for gene therapy or gene therapy to restore the deficient TIMP-3 may prevent progressive cardio-dilatation of dilated cardiomyopathy.