Opstad Trine B, Arnesen Harald, Pettersen Alf Å, Seljeflot Ingebjørg
Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Oslo, Norway; Center for Heart Failure Research, Oslo University Hospital, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway.
Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Oslo, Norway; Center for Heart Failure Research, Oslo University Hospital, Oslo, Norway.
PLoS One. 2014 Sep 5;9(9):e106816. doi: 10.1371/journal.pone.0106816. eCollection 2014.
Elevated levels of matrix metalloproteinase (MMP)-9 have been associated with the metabolic syndrome (MetS) and cardiovascular events. The MMP-9 -1562 C/T polymorphism has furthermore been shown as a risk factor for coronary artery disease (CAD). The non-favourable cardiometabolic state in MetS may increase the risk. We aimed to investigate the influence of MMP-9 -1562 C/T polymorphism in subjects with CAD and MetS.
Patients (n = 1000) with verified CAD stratified in Mets +/- (n = 244/756), were analyzed for the MMP-9 -1562 C/T polymorphism and related to clinical events after 2 years follow-up. Serum levels of total MMP-9 and tissue inhibitor of matrix metalloproteinases (TIMP)-1 were analyzed in all, whereas MMP-9 activity, extracellular matrix metalloproteinase inducer (EMMPRIN), and expression of the two genes were analyzed in a subset of 240 randomly selected patients.
Totally, 106 clinical endpoints were recorded. In MetS; the T-allele associated with 5.5 fold increase in event rate (p<0.0001), increased with number of MetS components, a 117% increase in total MMP-9 levels (TT homozygous, p = 0.05), significantly higher total- and endogenous active MMP-9 and TIMP-1 levels (p<0.01 all), and EMMPRIN was inversely correlated with pro- and endogenous active MMP-9 (p<0.05, both). In non-MetS; the T-allele was not associated with new events, nor higher MMP-9 levels. EMMPRIN was significantly correlated with total MMP-9 and TIMP-1 (p<0.01, both) and the two genes were inter-correlated (p<0.001).
In CAD patients with MetS, the MMP-9 T-allele increased the risk of clinical events, probably mediated through elevated MMP-9 levels and altered MMP-9 regulation.
基质金属蛋白酶（MMP）-9水平升高与代谢综合征（MetS）及心血管事件相关。此外，MMP-9 -1562 C/T多态性已被证明是冠状动脉疾病（CAD）的危险因素。MetS中不利的心脏代谢状态可能会增加风险。我们旨在研究MMP-9 -1562 C/T多态性对CAD和MetS患者的影响。
对确诊为CAD的患者（n = 1000）按照是否患有MetS分为两组（n = 244/756），分析MMP-9 -1562 C/T多态性，并在随访2年后与临床事件进行关联分析。对所有患者分析血清总MMP-9和基质金属蛋白酶组织抑制剂（TIMP）-1水平，而对随机选择的240例患者亚组分析MMP-9活性、细胞外基质金属蛋白酶诱导剂（EMMPRIN）以及这两个基因的表达。
共记录到106个临床终点。在MetS患者中，T等位基因与事件发生率增加5.5倍相关（p<0.0001），随MetS组分数量增加而增加，总MMP-9水平增加117%（TT纯合子，p = 0.05），总及内源性活性MMP-9和TIMP-1水平显著更高（均p<0.01），且EMMPRIN与前体及内源性活性MMP-9呈负相关（均p<0.05）。在非MetS患者中，T等位基因与新事件无关，MMP-9水平也未升高。EMMPRIN与总MMP-9和TIMP-1显著相关（均p<0.01），且这两个基因相互关联（p<0.001）。
在患有MetS的CAD患者中，MMP-9 T等位基因增加了临床事件风险，可能是通过升高MMP-9水平及改变MMP-9调节介导的。
