Role of matrix metalloproteinase (MMP)-2 in regulating smooth muscle contraction

基质金属蛋白酶(MMPs)是一种已知的蛋白质，通过将其他蛋白质切割成更小的片段，导致血管结构和功能的变化。基质金属蛋白酶-2广泛存在于血管平滑肌和血管内皮细胞中，并因其在血管收缩调节中的重要作用而被研究。MMPs是在没有任何活性的情况下产生的，它们需要其他蛋白质或氧化应激来激活它们。 舒尔茨实验室是第一个证明心肌细胞内的基质金属蛋白酶-2被氧化应激激活的实验室。一旦被激活，基质金属蛋白酶-2就会破坏肌钙蛋白和肌钙蛋白等对正常心肌收缩至关重要的蛋白质。因此，我们想测试血管中是否有类似的靶向收缩蛋白，这些蛋白容易被基质金属蛋白酶-2破坏，以及这是否会影响血管的收缩。 Calponin、Smovelelin-B和Smitin是在平滑肌细胞中发现的收缩蛋白，在结构上与肌钙蛋白和Titin相似。它们有助于维持收缩和保持血压正常。由于心肌细胞内肌钙蛋白和肌动蛋白被基质金属蛋白酶-2破坏，因此，肌钙蛋白、肌钙蛋白-B和肌动蛋白可能是基质金属蛋白酶-2作用的靶点，从而导致收缩功能减退和低血压。 我们发现，在细菌毒素诱导的氧化应激过程中，大鼠血管中的基质金属蛋白酶-2被激活，而基质金属蛋白酶抑制剂药物改善了这些大鼠的血管收缩。这导致我们的实验室测试了基质金属蛋白酶-2是否会裂解血管平滑肌中的收缩蛋白，并导致收缩功能的丧失。我们希望在这项提案中测试一个令人兴奋的新概念，即激活基质金属蛋白酶-2可能会破坏控制正常血管平滑肌收缩的关键蛋白。这一重要思想可能有助于我们理解控制血压的机制以及调节血压的新的药理学方法。

Matrix metalloproteinases (MMPs) are proteins known to cause structural and functional changes in blood vessels by cutting other proteins into smaller pieces. MMP-2 is found in vascular smooth muscle and endothelial cells and has been studied for its important role in the regulation of vascular contraction. MMPs are produced without any activity and they need other proteins or oxidative stress to activate them. The Schulz lab was the first to show that MMP-2 is activated within cardiac cells by oxidative stress. Once activated, MMP-2 destroys proteins such as troponin and titin which are essential for normal heart muscle contraction. Thus we thought to test if there are similarly targeted contractile proteins in blood vessels which are susceptible to destruction by MMP-2 and if this affects the contraction of blood vessels. Calponin, smoothelin-B and smitin are contractile proteins found in smooth muscle cells which are structurally similar to troponin and titin. They help to maintain constriction and keep blood pressure normal. As troponin and titin are destroyed by MMP-2 in cardiac cells, calponin, smoothelin-B and smitin may be targets of MMP-2 in smooth muscle cells which may result in poor contractile function and low blood pressure. We showed that MMP-2 is activated in rat blood vessels during oxidative stress induced by bacterial toxins and that MMP inhibitor drugs improved vascular contraction in these rats. This led our lab to test if MMP-2 cleaves contractile proteins in vascular smooth muscle and contributes to the loss of contractile function. We wish to test in this proposal an exciting and novel concept that activated MMP-2 may destroy key proteins that control normal vascular smooth muscle contraction. This important idea may help us in the understanding of mechanisms involved in controlling blood pressure and new pharmacological approaches to regulate it.