Schmidt Roland, Bültmann Andreas, Ungerer Martin, Joghetaei Nader, Bülbül Ozgür, Thieme Sven, Chavakis Triantafyllos, Toole Bryan P, Gawaz Meinrad, Schömig Albert, May Andreas E
Deutsches Herzzentrum und Medizinische Klinik I, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Circulation. 2006 Feb 14;113(6):834-41. doi: 10.1161/CIRCULATIONAHA.105.568162. Epub 2006 Feb 6.
Matrix metalloproteinases (MMPs) are thought to promote progression of atherosclerosis and cardiovascular complications such as plaque rupture. It has been suggested that, on tumor cells, the extracellular MMP inducer (EMMPRIN) is involved in MMP synthesis by as yet unknown mechanisms. On cardiovascular cells, regulation of EMMPRIN in vivo or any functional relevance for MMP induction in vitro has not yet been studied. Thus, we studied EMMPRIN expression on monocytes in acute myocardial infarction (MI) and its potential relevance for MMP activation.
In 20 patients with acute MI, surface expression of EMMPRIN was significantly enhanced on monocytes compared with in 20 patients with chronic stable angina. EMMPRIN upregulation was associated with increased expression of the membrane type 1 MMP (MT1-MMP) on monocytes (flow cytometry) as well as MMP-9 activity (gelatin zymography) in the plasma. At 6 months after successful revascularization, EMMPRIN, MT1-MMP, and MMP-9 had normalized. The secretion of MMP-9 by monocytes was induced by monocyte adhesion to immobilized recombinant EMMPRIN or to EMMPRIN-transfected Chinese hamster ovary cells. Moreover, adherent EMMPRIN-transfected monocytic cells stimulated MMP-2 activity of human vascular smooth muscle cells. Gene silencing of EMMPRIN by small-interfering RNA hindered lipopolysaccharide-induced monocyte secretion of MMP-9, indicating a predominant role of EMMPRIN in MMP-9 induction.
EMMPRIN and MT1-MMP are upregulated on monocytes in acute MI. During cellular interactions, EMMPRIN stimulates MMP-9 in monocytes and MMP-2 in smooth muscle cells, indicating that EMMPRIN may display a key regulatory role for MMP activity in cardiovascular pathologies.
基质金属蛋白酶（MMPs）被认为可促进动脉粥样硬化进展及心血管并发症，如斑块破裂。有研究表明，在肿瘤细胞上，细胞外MMP诱导剂（EMMPRIN）通过尚不明确的机制参与MMP合成。在心血管细胞上，体内EMMPRIN的调节或其在体外对MMP诱导的任何功能相关性尚未得到研究。因此，我们研究了急性心肌梗死（MI）患者单核细胞上EMMPRIN的表达及其与MMP激活的潜在相关性。
在20例急性MI患者中，与20例慢性稳定型心绞痛患者相比，单核细胞上EMMPRIN的表面表达显著增强。EMMPRIN上调与单核细胞上膜型1 MMP（MT1-MMP）表达增加（流式细胞术）以及血浆中MMP-9活性增加（明胶酶谱法）相关。成功血运重建后6个月，EMMPRIN、MT1-MMP和MMP-9恢复正常。单核细胞对固定化重组EMMPRIN或EMMPRIN转染的中国仓鼠卵巢细胞的黏附可诱导MMP-9分泌。此外，贴壁的EMMPRIN转染单核细胞刺激人血管平滑肌细胞的MMP-2活性。小干扰RNA对EMMPRIN的基因沉默阻碍了脂多糖诱导的单核细胞MMP-9分泌，表明EMMPRIN在MMP-9诱导中起主要作用。
急性MI患者单核细胞上EMMPRIN和MT1-MMP上调。在细胞相互作用过程中，EMMPRIN刺激单核细胞中的MMP-9和平滑肌细胞中的MMP-2，表明EMMPRIN可能在心血管疾病中对MMP活性发挥关键调节作用。
