Suppression of NADPH oxidase-derived Oxidative Stress by Anti-sense Probes and HDL in Human Vascular Endothelium

在澳大利亚，导致心脏病发作的冠心病(CHD)仍然是最大的死亡原因，每年夺走2.8万人的生命。氧化应激是导致动脉中氧自由基产生增加的原因，是导致冠心病、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所有动脉衬里的关键细胞中产生的，这些细胞被称为血管内皮细胞。通过使用我们实验室开发的新型DNA类型分子(称为反义分子)来阻止导致氧化应激的特定基因，我们将确定该基因是否对培养中生长的人和小鼠细胞中氧自由基的形成负责。此外，我们还将探索该基因是否被已知的与冠心病相关的因素所启动。最后，我们还将调查被称为高密度脂蛋白的良好胆固醇是否可以防止人类细胞中的氧化应激，正如我们在活体动脉中发现的那样。如果我们发现它对内皮有同样的保护作用，我们将确定它是如何做到这一点的，以及高密度脂蛋白颗粒的哪些成分蛋白质是重要的。这可能会提出新的治疗方法，以防止导致心脏病发作和中风的急性事件，并可能在急性氧化应激导致损害的新应用中，例如在中风发生后不久的大脑中。我们还计划开发反义药物，专门针对受影响的内皮细胞中的重要基因。此外，我们还有其他特定的新药可以阻断动脉中的这一系统。同时，我们将在动脉疾病的小鼠和兔模型中测试该基因的作用，因为我们的两种药物都可能提供有价值的新治疗药物，以针对CHD的根本原因，而不是像目前的药物那样仅仅针对其症状。

In Australia, coronary heart disease (CHD) causing heart attacks remains 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, is an important cause of CHD, heart attacks and strokes. We seek to understand how such oxyradicals are produced in the key cells that form the lining of all arteries, known as the vascular endothelium. By using novel DNA-type molecules (known as anti-sense) developed in our laboratory, which block a particular gene causing oxidative stress, we will determine whether this gene is responsible for the formation of oxyradicals in human and mouse cells grown in culture. In addition, we will explore whether this gene is turned on by factors known to be involved in CHD. Finally, we will also investigate whether the good cholesterol known as HDL can act to prevent oxidative stress in human cells, as we discovered it appears to do in living arteries in vivo. If we find it has the same protective effect in endothelium, we will determine how it does this, and which component proteins of the HDL particle are important. This might suggest new treatments to prevent acute events leading to heart attack and stroke, and possibly new applications where damage appears to result from acute oxidative stress, such as in the brain soon after a stroke has occurred. We also have a plan to develop antisense drugs that will target the important gene specifically in the affected endothelium. In addition, we have other specific new drugs that will block this system in arteries. Simultaneously we will be testing the role of this gene in mouse and rabbit models of artery disease, for both our types of drugs might provide valuable new therapeutic agents to target the underlying cause of CHD and not just its symptoms as current drugs do.