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3.1 MMP9与糖尿病动脉粥样硬化
大血管病变是2型糖尿病的主要慢性并发症,也是2型糖尿病死亡的主要原因,其基本病理变化是动脉粥样硬化。动脉粥样硬化过程中,血管内皮细胞、平滑肌细胞、巨噬细胞、泡沫细胞均能合成和分泌MMP9,尤以巨噬细胞作用最强,MMP9降解基底膜,利于单核细胞入侵,加速oxLDL渗透。使糖尿病动脉粥样斑块较非糖尿病者更不稳定。众多研究表明2型糖尿病合并AS病变者MMP9水平较单纯2型糖尿病者或单纯AS者明显升高。在动物模型中，Uemura等[14]用明胶酶谱及Western印迹分析、电子顺磁共振等检测发现,不管是1型还是2型啮齿类糖尿病动物模型,其血管组织和血浆中MMP9均明显升高。Camp等[15]用酶谱分析方法观察到与非糖尿病野生型鼠相比,糖尿病野生鼠血浆和左心室中MMP9的活性升高。而对糖尿病鼠而言,不管是野生型还是MMP9基因敲除鼠,心脏组织型TIMP的浓度均减少。而且MMP9活性的升高与心脏内皮功能紊乱密切相关。在人体，李佳等[16]报道, 2型糖尿病患者血清MMP9含量明显高于非糖尿病患者,治疗4周时,MMP9水平即明显下降,且其降低与HbA1c的降低呈正相关。在分子水平，Death等[17]也发现高糖培养可导致内皮细胞和单核细胞MMP/TIMP系统表达失衡,特别是可使单核巨噬细胞MMP9表达和活性升高(P<0.05),加速糖尿病AS的形成并降低斑块稳定性。另外MMPs基因多态性与糖尿病大血管病变的发生有密切关系。刘宽芝等[18]发现与对照组和2型糖尿病组相比,大血管病变组的T等位基因和TT等位基因型频率显著高于健康对照组和无并发症组。
糖尿病引起MMP9升高的机制目前研究主要集中在氧化低密度脂蛋白(OxLDL)和某些细胞因子的作用。糖尿病机体中低密度脂蛋白(LDL)的糖化和氧化明显增加，OxLDL可直接上调单核细胞源性的巨噬细胞中MMP9的表达,而高密度脂蛋白(HDLC)可阻断OxLDL的上述效应。2型糖尿病患者往往存在不同程度的IR,使高血压的发病率显著上升,长期的高血压可使血管内皮功能受损,加速糖尿病血管病变的发生、发展。陈雅静等[19]报道, 2型糖尿病患者血清MMP9含量明显升高,其升高程度与血压呈正相关。糖尿病引起MMP9升高的具体机制的研究尚处于初步阶段，有待进一步探索。
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