CNR Clinical Physiology Institute, Cardiovascular Department, Niguarda Cà Granda Hospital Milan, Milan, Italy.
Circ J. 2011;75(10):2387-96. doi: 10.1253/circj.cj-11-0118. Epub 2011 Aug 4.
Redox aminothiols have been reported to modulate the activity of recombinant metalloproteinases (MMP). The aim of the present study was to investigate the effects of myocardial redox state on the activities of MMP-2 and -9 implicated in cardiac remodeling in end-stage heart failure patients supported by left ventricular assist device (LVAD).
During heart transplant (HT) surgery, myocardial specimens (MS) from right ventricular walls and LV walls were obtained from 7 LVAD recipients (LVAD group, MS n=35) and from 7 stable HT candidates on medical therapy (MT group, MS n=35). Myocardial MMP-2 and -9 activities and expression, tissue inhibitor of MMP (TIMP)-1 and -4, transforming growth factor (TGF)-β1 and aminothiol concentrations were measured. MMP-2 and -9 activities were evaluated also by incubating MS with different amounts of reduced and oxidized glutathione (GSH). MMP-2 and -9 activities and expression were lower in the LVAD group, whereas myocardial TIMP-1 and -4 concentrations were comparable to those of MT patients. Higher GSH and TGF-β1 concentrations were found in LVAD-recipients. Only GSH concentrations were inversely related to MMP-2 and -9 activities. In vitro, GSH had an inhibitory effect on MMP-2 and -9 activities.
LVAD recipients show reduced myocardial MMP-2 and -9 activities and expression when compared to medically treated patients. Changes of myocardial redox state, predominantly GSH-dependent, appear to modulate MMP-2 and -9 activities by an inhibitory effect dependent on thiol content. These data support a role of GSH cycle in modulating the extracellular matrix in end-stage heart failure patients supported by LVAD.
氧化还原氨基硫醇已被报道可调节重组金属蛋白酶（MMP）的活性。本研究旨在探讨心肌氧化还原状态对左心室辅助装置（LVAD）支持的终末期心力衰竭患者心脏重构中涉及的 MMP-2 和 MMP-9 活性的影响。
在心脏移植（HT）手术期间，从 7 名 LVAD 受体（LVAD 组，MS n=35）和 7 名接受药物治疗的稳定 HT 候选者（MT 组，MS n=35）的右心室壁和 LV 壁获得心肌标本（MS）。测量心肌 MMP-2 和 MMP-9 活性和表达、基质金属蛋白酶抑制剂（TIMP）-1 和 -4、转化生长因子（TGF）-β1 和氨基硫醇浓度。还通过用不同量的还原型和氧化型谷胱甘肽（GSH）孵育 MS 来评估 MMP-2 和 MMP-9 的活性。与 MT 患者相比，LVAD 组的 MMP-2 和 MMP-9 活性和表达较低，而心肌 TIMP-1 和 -4 浓度相当。LVAD 受体中发现较高的 GSH 和 TGF-β1 浓度。只有 GSH 浓度与 MMP-2 和 MMP-9 活性呈负相关。在体外，GSH 对 MMP-2 和 MMP-9 活性具有抑制作用。
与接受药物治疗的患者相比，LVAD 受体的心肌 MMP-2 和 MMP-9 活性和表达降低。心肌氧化还原状态的变化，主要是 GSH 依赖性的，似乎通过依赖巯基含量的抑制作用来调节 MMP-2 和 MMP-9 活性。这些数据支持 GSH 循环在调节 LVAD 支持的终末期心力衰竭患者细胞外基质中的作用。
