Targetting the NADPHoxidase source of reactive oxygen species in vascular disease

在澳大利亚，导致心脏病发作或中风的冠心病（CHD）是最大的死亡原因，每年夺去28，000人的生命。氧化应激，由于动脉中氧自由基的产生增加，似乎是冠心病、心脏病发作和中风的重要原因。我们试图了解这些氧自由基是如何在构成动脉壁的细胞中产生的。利用新型DNA分子，我们最近发现一种名为Nox 4的蛋白质对血管产生氧自由基至关重要。此外，我们已经确定了一类选择性阻断血管中Nox 4活性的药物。我们现在希望直接测试抑制Nox 4是否可以预防动物模型中CHD的发展，无论是用DNA型分子，已知阻断Nox 4的各种药物，还是通过完全消除小鼠中的Nox 4基因。这项工作不仅将促进我们对血管氧化损伤起源的理解，而且还将使我们能够确定治疗与氧化应激增加相关的心血管疾病的新治疗靶点。同样的药物和分子也可能被证明对改善心脏病发作和中风的恢复有用，因为在这些情况下，心脏和大脑中的Nox4可能会被打开。本研究所获得的信息将有助于指导未来冠心病和中风临床管理的处方实践，并设计新的冠心病治疗化合物。

In Australia, coronary heart disease (CHD) leading to heart attacks or strokes is the largest cause of death, claiming a staggering 28,000 lives a year. Oxidative stress, resulting from increased production of oxygen free radicals in arteries, appears to be an important cause of CHD, heart attacks and strokes. We seek to understand how such oxyradicals are produced in the cells that make up the artery wall. Using novel DNA-type molecules we have recently discovered that a protein called Nox4 is crucial for the production of oxygen free radicals by blood vessels. Furthermore, we have identified a class of drugs that selectively block the activity of Nox4 in blood vessels. We now wish to directly test whether inhibiting Nox4, either with DNA-type molecules, various drugs known to block Nox4, or by complete elimination of the Nox4 gene in mice, prevents the development of CHD in animal models. This work will not only advance our understanding of the origin of vascular oxidative damage but will also allow us to identify novel therapeutic targets in the treatment of cardiovascular diseases that are associated with increased oxidative stress. The same drugs and molecules might also prove useful for improving recovery from heart attacks and strokes, for Nox4 may be turned on in the heart and brain in these conditions. Information obtained in our study will be useful in directing future prescription practices in clinical management of CHD and stroke, and for designing new therapeutic compounds for CHD.