Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Solna, Stockholm, Sweden.
Int J Mol Med. 2011 Aug;28(2):247-53. doi: 10.3892/ijmm.2011.693. Epub 2011 May 6.
Matrix-degrading proteases capable of degrading components of the extracellular matrix may play an important role in development and progression of atherosclerotic lesions. In the present study, we used the Ldlr(-/-)Apob(100/100) mouse model, which has a plasma lipoprotein profile similar to that of humans with atherosclerosis, to study the expression of matrix metalloproteinases (MMPs) during early stages of atherosclerosis development. We analyzed the expression of 11 proteases and three protease inhibitors in 5- to 40-week-old Ldlr(-/-)Apob(100/100) mice. Expression and activity of MMP-2 and MMP-9 was increased in advanced atherosclerotic lesions followed by macrophage infiltration as shown by real-time PCR, gel-based and in situ zymography and immunohistochemistry. Expression of other investigated MMPs did not increase during disease progression. However, the mRNA expression of MMP-8 and MMP-13 was down-regulated, which could explain the relatively high amount of collagen observed in the vessels in this model. In conclusion, low proteolytic expression at early stages of atherogenesis and a limited repertoire of proteolytic enzymes were associated with the progression of atherosclerosis in Ldlr(-/-)Apob(100/100) mice. The study suggests that MMP-2 and MMP-9 are the main proteases involved in atherogenesis in this mouse model.
能够降解细胞外基质成分的基质降解蛋白酶可能在动脉粥样硬化病变的发展和进展中发挥重要作用。在本研究中，我们使用了具有与人动脉粥样硬化相似的血浆脂蛋白谱的 Ldlr(-/-)Apob(100/100)小鼠模型，研究了基质金属蛋白酶（MMPs）在动脉粥样硬化发展早期的表达。我们分析了 5 至 40 周龄 Ldlr(-/-)Apob(100/100)小鼠中 11 种蛋白酶和 3 种蛋白酶抑制剂的表达。实时 PCR、凝胶基和原位酶谱及免疫组织化学显示，MMP-2 和 MMP-9 的表达和活性在晚期动脉粥样硬化病变中增加，随后巨噬细胞浸润。其他研究的 MMPs 的表达在疾病进展过程中没有增加。然而，MMP-8 和 MMP-13 的 mRNA 表达下调，这可以解释在该模型中观察到的相对大量的胶原。总之，在动脉粥样硬化发生的早期阶段低蛋白水解表达和有限的蛋白水解酶谱与 Ldlr(-/-)Apob(100/100)小鼠的动脉粥样硬化进展相关。该研究表明，MMP-2 和 MMP-9 是该小鼠模型中动脉粥样形成的主要蛋白酶。
