Sasaguri Y, Murahashi N, Sugama K, Kato S, Hiraoka K, Satoh T, Isomoto H, Morimatsu M
Department of Pathology, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan.
Lab Invest. 1994 Aug;71(2):261-9.
It is known that extracellular matrix-degrading enzymes play an important role in tissue remodeling and that large amounts of structural proteins including types I, III, IV, and V collagens and elastin are produced by smooth muscle cells (SMC) in the arterial wall. We have recently shown that matrix metalloproteinases (MMPs) produced by human aortic medial smooth muscle cells are closely related to the proliferation of the cells, leading to the formation of atherosclerotic plaques, characteristic of intimal remodeling. For a better understanding of the mechanism of atherogenesis, therefore, it is important to clarify the relationship between the production of matrix-degrading enzymes and artery development.
In vivo or in vitro synthesis of MMPs by SMC was analyzed by immunohistochemistry and immunoblotting. Elastase activity in the culture medium was also estimated.
Production of proMMP 1, 2, and 3 was detected in cultured SMC isolated from the aortas of both neonates and fetuses; in medial SMC cultured from young individuals, production of proMMP-1 and -3 was extremely decreased, but was apparent in intimal SMC. Immunohistochemical observation indicated that in the media of fetal or neonatal aorta, SMC synthesized large amounts of the three proMMPs; in aortas from older individuals, proMMP-2, but not proMMP-1 and -3, was detected in the media, and relatively large amounts of proMMP-1, -2, and -3 were produced by SMC in the slightly thickened intima. Assay of elastase activity in the culture medium gave results similar to those for MMPs.
We conclude that the production of proMMP-1 and -3 is associated with phenotypic modulation of SMC to a "synthetic" state, and that the ability of SMC to produce MMPs plays an important role in the development and/or aging of the human aorta through remodeling of the extracellular matrix; furthermore elastase is also involved in these processes in the arterial wall.
已知细胞外基质降解酶在组织重塑中起重要作用，并且动脉壁中的平滑肌细胞（SMC）会产生大量包括I、III、IV和V型胶原蛋白以及弹性蛋白在内的结构蛋白。我们最近发现，人主动脉中膜平滑肌细胞产生的基质金属蛋白酶（MMP）与细胞增殖密切相关，导致动脉粥样硬化斑块的形成，这是内膜重塑的特征。因此，为了更好地理解动脉粥样硬化的发病机制，阐明基质降解酶的产生与动脉发育之间的关系很重要。
通过免疫组织化学和免疫印迹分析SMC在体内或体外产生MMP的情况。还评估了培养基中的弹性蛋白酶活性。
在从新生儿和胎儿主动脉分离的培养SMC中检测到前MMP 1、2和3的产生；在从年轻人培养的中膜SMC中，前MMP-1和-3的产生极度减少，但在内膜SMC中很明显。免疫组织化学观察表明，在胎儿或新生儿主动脉的中膜中，SMC合成了大量的三种前MMP；在老年个体的主动脉中，在中膜中检测到前MMP-2，但未检测到前MMP-1和-3，并且在内膜略增厚处的SMC产生了相对大量的前MMP-1、-2和-3。培养基中弹性蛋白酶活性的测定结果与MMP的结果相似。
我们得出结论，前MMP-1和-3的产生与SMC向“合成”状态的表型调节有关，并且SMC产生MMP的能力通过细胞外基质重塑在人类主动脉的发育和/或衰老中起重要作用；此外，弹性蛋白酶也参与动脉壁中的这些过程。
