Homocysteine-mediated activation and mitochondrial translocation of calpain regulates MMP-9 in MVEC
Homocysteine-mediated activation and mitochondrial translocation of calpain regulates MMP-9 in MVEC
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DOI：
10.1152/ajpheart.00377.2006
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发表时间：
2006-12-01
影响因子：
4.8
通讯作者：
Tyagi, Suresh C.
中科院分区：
文献类型：
--
作者：
Moshal, Karni S.;Singh, Mahavir;Tyagi, Suresh C.
高同型半胱氨酸血症（HHCy）与动脉粥样硬化、中风和痴呆有关。同型半胱氨酸通过激活基质金属蛋白酶-9（MMP-9）引起细胞外基质重塑，部分通过诱导氧化还原信号和调节细胞内钙动力学。钙蛋白酶是钙依赖性半胱氨酸蛋白酶，其通过氧化爆发参与线粒体损伤。线粒体异常已被确定在HHcy。Hcy通过线粒体途径激活MMP-9诱导细胞外基质重塑的机制在很大程度上是未知的。我们报告了一个新的作用，钙蛋白酶在心肌细胞介导的MMP-9激活同型半胱氨酸在培养的大鼠心脏微血管内皮细胞。我们的观察表明，钙蛋白酶调节Hcy诱导的MMP-9的表达和活性。我们发现，同型半胱氨酸激活钙蛋白酶-1，但不是钙蛋白酶-2，在钙依赖性的方式。有趣的是，钙蛋白酶活性的增强并没有反映在其内源性抑制剂钙蛋白酶抑制素水平的降低上。我们提出的证据表明，同型半胱氨酸诱导活性钙蛋白酶从胞质到线粒体的易位，导致MMP-9激活，部分原因是引起线粒体内的氧化爆发。此外，对钙蛋白酶（钙蛋白酶和钙蛋白酶-1抑制剂）、ERK（PD-98059）和线粒体解偶联剂FCCP的药理学抑制剂的研究表明，钙蛋白酶和ERK-1/2是Hcy/MMP-9信号轴中的主要事件，线粒体内氧化应激通过ERK-1/2信号级联调节MMP-9。总之，这些发现确定了线粒体易位的钙蛋白酶-1在MMP-9激活在HHcy期间的新作用，部分，通过增加线粒体氧化应激。
Hyperhomocysteinemia (HHcy) is associated with atherosclerosis, stroke, and dementia. Hcy causes extracellular matrix remodeling by the activation of matrix metalloproteinase-9 (MMP-9), in part, by inducing redox signaling and modulating the intracellular calcium dynamics. Calpains are the calcium-dependent cysteine proteases that are implicated in mitochondrial damage via oxidative burst. Mitochondrial abnormalities have been identified in HHcy. The mechanism of Hcy-induced extracellular matrix remodeling by MMP-9 activation via mitochondrial pathway is largely unknown. We report a novel role of calpains in mitochondrial-mediated MMP-9 activation by Hcy in cultured rat heart microvascular endothelial cells. Our observations suggested that calpain regulates Hcy-induced MMP-9 expression and activity. We showed that Hcy activates calpain-1, but not calpain-2, in a calcium-dependent manner. Interestingly, the enhanced calpain activity was not mirrored by the decreased levels of its endogenous inhibitor calpastatin. We presented evidence that Hcy induces the translocation of active calpain from cytosol to mitochondria, leading to MMP-9 activation, in part, by causing intramitochondrial oxidative burst. Furthermore, studies with pharmacological inhibitors of calpain ( calpeptin and calpain-1 inhibitor), ERK (PD-98059) and the mitochondrial uncoupler FCCP suggested that calpain and ERK-1/2 are the major events within the Hcy/MMP-9 signal axis and that intramitochondrial oxidative stress regulates MMP-9 via ERK-1/2 signal cascade. Taken together, these findings determine the novel role of mitochondrial translocation of calpain-1 in MMP-9 activation during HHcy, in part, by increasing mitochondrial oxidative tress.