Barton Paul J R, Birks Emma J, Felkin Leanne E, Cullen Martin E, Koban Maren U, Yacoub Magdi H
Heart Science Centre, Royal Brompton and Harefield Hospital, Harefield, Middlesex, United Kingdom
J Heart Lung Transplant. 2003 Jul;22(7):738-44. doi: 10.1016/s1053-2498(02)00557-0.
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.
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.
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.
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.
作者之前对接受左心室辅助装置（LVAD）植入的心力衰竭病情恶化患者与终末期稳定心力衰竭（ESF）患者心肌中的基因表达变化进行了鉴定和比较。我们推测基质金属蛋白酶（MMPs）及其内源性抑制剂——基质金属蛋白酶组织抑制剂（TIMPs）——与心力衰竭病情恶化的潜在机制有关。
使用网格宏阵列滤膜对心力衰竭中MMP和TIMP mRNA表达进行全面概述。通过对27例接受LVAD植入的心力衰竭病情恶化患者、17例接受择期心脏移植的终末期稳定心力衰竭患者以及28个具有良好血流动力学功能的供体器官的心肌样本进行定量实时逆转录聚合酶链反应（RT-PCR），测定TIMP1、MMP1和β-血影蛋白的精确mRNA水平。
对合并的衰竭心脏样本进行网格宏阵列分析确定，TIMP1 mRNA是衰竭心肌中最易检测到的TIMP。定量RT-PCR显示，终末期稳定心力衰竭患者（1.00±0.24，n = 17）和供体器官样本（1.49±0.22，n = 28）中个体患者的表达水平相似，但在心力衰竭病情恶化组中显著升高（5.38±0.32，n = 26，与终末期稳定心力衰竭患者相比，p < 0.0001）。同样，供体组和终末期稳定心力衰竭组之间的MMP1水平无差异，但在心力衰竭病情恶化组中升高（6.04±0.50，n = 27，与终末期稳定心力衰竭组相比，p < 0.001）。所有3组中的β-II血影蛋白水平相同。在单独考虑所有患者时，TIMP1和MMP1彼此之间以及与该患者系列中先前测定的白细胞介素-1β（IL-1β）和IL-6的mRNA水平均呈正相关，但两者均与肿瘤坏死因子α无关。
心力衰竭病情恶化患者的TIMP1和MMP1 mRNA表达增加。与促炎细胞因子的相关性表明存在共同的调节途径以及IL-6和IL1-β的潜在激活作用。
