Romanic A M, Burns-Kurtis C L, Gout B, Berrebi-Bertrand I, Ohlstein E H
Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406, USA.
Life Sci. 2001 Jan 5;68(7):799-814. doi: 10.1016/s0024-3205(00)00982-6.
Myocardial infarction (MI), leads to cardiac remodeling, thinning of the ventricle wall, ventricular dilation, and heart failure, and is a leading cause of death. Interactions between the contractile elements of the cardiac myocytes and the extracellular matrix (ECM) help maintain myocyte alignment required for the structural and functional integrity of the heart. Following MI, reorganization of the ECM and the myocytes occurs, contributing to loss of heart function. In certain pathological circumstances, the ECM is modulated such that the structure of the tissue becomes damaged. The matrix metalloproteinases (MMPs) are a family of enzymes that degrade molecules of the ECM. The present experiments were performed to define the time-course, isozyme subtypes, and cellular source of increased MMP expression that occurs following MI in an experimental rabbit model. Heart tissue samples from infarcted and sham animals were analyzed over a time-course of 1-14 days. By zymography, it was demonstrated that, unlike the sham controls, MMP-9 expression was induced within 24 hours following MI. MMP-3 expression, also absent in sham controls, was induced 2 days after MI. MMP-2 expression was detected in both the sham and infarcted samples and was modestly up-regulated following MI. Tissue inhibitor of metalloproteinase-1 (TIMP-1) expression was evaluated and shown to be down-regulated following MI, inverse of MMP-9 and MMP-3 expression. Further, MMP-9 and MMP-3 expression was detected by immunohistochemistry in myocytes within the infarct. Additional studies were conducted in which cultured rat cardiac myocytes were exposed to a hypoxic environment (2% O2) for 24 hours and the media analyzed for MMP expression. MMP-9 and MMP-3 were induced following exposure to hypoxia. It is speculated that the net increase in proteolytic activity by myocytes is a contributing factor leading to myocyte misalignment and slippage. Additional studies with a MMP inhibitor would elucidate this hypothesis.
心肌梗死（MI）会导致心脏重塑、心室壁变薄、心室扩张和心力衰竭，是主要的死亡原因。心肌细胞的收缩元件与细胞外基质（ECM）之间的相互作用有助于维持心脏结构和功能完整性所需的心肌细胞排列。MI后，ECM和心肌细胞会发生重组，导致心脏功能丧失。在某些病理情况下，ECM会被调节，从而使组织结构受损。基质金属蛋白酶（MMPs）是一类降解ECM分子的酶。本实验旨在确定实验性兔模型MI后MMP表达增加的时间进程、同工酶亚型和细胞来源。在1至14天的时间进程中，对梗死动物和假手术动物的心脏组织样本进行了分析。通过酶谱分析表明，与假手术对照组不同，MI后24小时内即诱导MMP-9表达。假手术对照组中也不存在的MMP-3表达在MI后2天被诱导。在假手术和梗死样本中均检测到MMP-2表达，且MI后有适度上调。对金属蛋白酶组织抑制剂-1（TIMP-1）表达进行了评估，结果显示MI后其表达下调，与MMP-9和MMP-3表达相反。此外，通过免疫组织化学在梗死区内的心肌细胞中检测到MMP-9和MMP-3表达。还进行了其他研究，将培养的大鼠心肌细胞暴露于低氧环境（2% O2）24小时，并分析培养基中的MMP表达。暴露于低氧环境后诱导了MMP-9和MMP-3表达。据推测，心肌细胞蛋白水解活性的净增加是导致心肌细胞排列紊乱和滑动的一个促成因素。使用MMP抑制剂的进一步研究将阐明这一假说。
