Increased expression of extracellular matrix regulators TIMP1 and MMP1 in deteriorating heart failure
Increased expression of extracellular matrix regulators TIMP1 and MMP1 in deteriorating heart failure
复制标题
DOI：
10.1016/s1053-2498(02)00557-0
复制
发表时间：
2003-07-01
影响因子：
8.9
通讯作者：
Yacoub, MH
中科院分区：
文献类型：
--
作者：
Barton, PJR;Birks, EJ;Yacoub, MH
背景：作者先前确定并比较了接受左心室辅助装置（LVAD）植入的恶化性心力衰竭患者与稳定终末期心力衰竭（ESF）患者心肌基因表达的变化。我们假设基质金属蛋白酶（MMPs）及其内源性抑制剂，即基质金属蛋白酶的组织抑制剂（TIMPs），可能与心衰恶化的机制有关。方法：使用网格宏观阵列过滤器提供心力衰竭中MMP和TIMP mRNA表达的广泛概述。采用实时定量逆转录聚合酶链反应（RT-PCR）对27例接受LVAD植入的恶化性心力衰竭患者、17例稳定ESF接受择期心脏移植的患者和28例血流动力学功能良好的供体器官的心肌样本进行精确的TIMP1、MMP1和β -spectrin mRNA水平的测定。结果：对合并的衰竭心脏样本进行网格宏观阵列分析，发现TIMP1 mRNA是衰竭心肌中最容易检测到的TIMP。定量RT-PCR结果显示，与ESF稳定组（1.00 +/- 0.24,n = 17）和供体器官样本（1.49 +/- 0.22,n = 28）相比，ESF恶化组（5.38 +/- 0.32,n = 26, p < 0.0001）的个体表达水平相似。同样，MMP1水平在供体组和ESF组之间没有差异，但恶化衰竭组升高（与ESF组相比，6.04 +/- 0.50,n = 27, p < 0.001）。三组的β - ii幽灵素水平相同。单独考虑所有患者时，TIMP1和MMP1彼此呈正相关，并且与先前测定的白细胞介素-1 β (il -1 β)和IL-6 mRNA水平呈正相关，但与肿瘤坏死因子α均不相关。结论：心力衰竭恶化患者TIMP1和MMP1 mRNA表达增加。与促炎细胞因子的相关性提示IL-6和il - 1- β调节和潜在激活的共同途径。
Background: The authors previously identified and compared alterations in gene expression in the myocardia of patients with deteriorating heart failure who underwent left ventricular assist device (LVAD) implantation with those of patients with stable end-stage failure (ESF). We hypothesized that matrix metalloproteinases (MMPs) and their endogenous inhibitors, the tissue inhibitors of MMPs (TIMPs), would be implicated in the mechanisms that underlie deteriorating heart failure.Methods: Gridded macro-array filters were used to provide a broad overview of MMP and TIMP mRNA expression in heart failure. Precise mRNA levels of TIMP1, MMP1, and beta-spectrin were determined using quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) of myocardial samples from 27 patients with deteriorating heart failure who underwent LVAD implantation, from 17 patients with stable ESF who underwent elective heart transplantation, and from 28 donor organs with good hemodynamic function.Results: Gridded macro-arrays analysis of pooled failing heart samples determined that TIMP1 mRNA was the most readily detectable TIMP in failing myocardium. Quantitative RT-PCR showed that expression levels in individual patients were similar in patients with stable ESF (1.00 +/- 0.24, n = 17) and in donor organ samples (1.49 +/- 0.22, n = 28) but were significantly increased in the deteriorating heart failure group (5.38 +/- 0.32, n = 26, p < 0.0001 compared with patients with ESF). Similarly, MMP1 levels did not differ between donor and ESF groups but increased in the deteriorating failure group (6.04 +/- 0.50, n = 27, p < 0.001 compared with the ESF group). Levels of beta-II spectrin were the same in all 3 groups. Both TIMP1 and MMP1 showed positive correlation with each other and with previously determined levels of mRNA for both interleukin-1beta (IL-1beta) and IL-6 in this patient series when considering all patients individually, but neither correlated with tumor necrosis factor alpha.Conclusions: Patients with deteriorating heart failure have increased expression of TIMP1 and MMP1 mRNA. Correlation with pro-inflammatory cytokines suggests common pathways of regulation and potential activation by IL-6 and IL1-beta.