Fedak Paul W M, Moravec Christine S, McCarthy Patrick M, Altamentova Svetlana M, Wong Amy P, Skrtic Marko, Verma Subodh, Weisel Richard D, Li Ren-Ke
General Research Institute, Division of Cardiac Surgery, University of Toronto, Toronto General Hospital, Toronto, Ontario, Canada.
Circulation. 2006 Jan 17;113(2):238-45. doi: 10.1161/CIRCULATIONAHA.105.571414. Epub 2006 Jan 9.
Disintegrin metalloproteinases (ADAMs) may contribute to structural cardiac remodeling by altering cell-surface matrix receptors (integrins) and activating potent biomolecules. We compared expression of ADAMs, their endogenous inhibitor tissue inhibitor of metalloproteinases (TIMP)-3, and integrins in human heart tissue with varied patterns of structural remodeling.
Myocardium was obtained from patients with dilated cardiomyopathy (n=20), hypertrophic obstructive cardiomyopathy (n=5), and nonfailing donor hearts (n=7). Paired samples (n=10) were obtained before left ventricular assist device insertion and at transplantation. The expressions of ADAM10, ADAM12, ADAM15, and ADAM17, TIMP-3, and integrin receptors beta1D and beta3 were determined by quantitative immunoblotting. Integrin shedding was assessed by the ratio of integrin cleavage products to intact protein abundance. Confocal microscopy was performed. Dilated cardiomyopathy was characterized by increased ADAM10 and ADAM15 expression and reduced TIMP-3 expression. The integrin beta1D cleavage ratio was elevated, indicating receptor shedding. ADAM10 and ADAM15 expressions correlated with the cleavage ratio. ADAM10 colocalized with integrin beta1D by confocal microscopy. ADAM10 expression correlated with clinical indices of chamber dilatation and systolic dysfunction. Hemodynamic unloading reduced ADAM10 and ADAM12 expressions and increased integrin beta1D expression. ADAM12 and integrin beta1D expressions were increased in HOCM. ADAM17 was increased in both dilated cardiomyopathy and hypertrophic obstructive cardiomyopathy.
Disintegrin metalloproteinases are differentially expressed in human myocardium, reflecting the underlying pattern of structural remodeling. ADAM10 and ADAM15 may contribute to cardiac dilatation by reducing cell-matrix interactions via integrin shedding. Targeting disintegrin metalloproteinases, perhaps by restoring deficient TIMP-3 levels with gene or cell-based therapies, may prevent progressive chamber dilatation in human dilated cardiomyopathy.
解整合素金属蛋白酶（ADAMs）可能通过改变细胞表面基质受体（整合素）和激活强效生物分子来促进心脏结构重塑。我们比较了解整合素金属蛋白酶、其内源性抑制剂金属蛋白酶组织抑制剂（TIMP）-3以及整合素在具有不同结构重塑模式的人类心脏组织中的表达。
从扩张型心肌病患者（n = 20）、肥厚型梗阻性心肌病患者（n = 5）和无功能障碍的供体心脏（n = 7）获取心肌组织。在植入左心室辅助装置前和移植时获取配对样本（n = 10）。通过定量免疫印迹法测定ADAM10、ADAM12、ADAM15和ADAM17、TIMP-3以及整合素受体β1D和β3的表达。通过整合素裂解产物与完整蛋白丰度的比值评估整合素脱落情况。进行共聚焦显微镜检查。扩张型心肌病的特征是ADAM10和ADAM15表达增加，TIMP-3表达降低。整合素β1D裂解率升高，表明受体脱落。ADAM10和ADAM15表达与裂解率相关。通过共聚焦显微镜检查，ADAM10与整合素β1D共定位。ADAM10表达与心室扩张和收缩功能障碍的临床指标相关。血流动力学卸载降低了ADAM10和ADAM12的表达，并增加了整合素β1D的表达。肥厚型梗阻性心肌病中ADAM12和整合素β1D表达增加。扩张型心肌病和肥厚型梗阻性心肌病中ADAM17均增加。
解整合素金属蛋白酶在人类心肌中存在差异表达，反映了潜在的结构重塑模式。ADAM10和ADAM15可能通过整合素脱落减少细胞-基质相互作用，从而导致心脏扩张。通过基因或基于细胞的疗法恢复不足的TIMP-3水平来靶向解整合素金属蛋白酶，可能预防人类扩张型心肌病中进行性心室扩张。
