Defining the roles of NADPH oxidases in vascular remodelling and arterial hypertension

高血压是心脏病发作、心力衰竭和中风等心血管疾病的主要危险因素，是全球死亡的主要原因，也是澳大利亚医疗保健预算的巨大负担。氧化应激是由血管壁内称为自由基的有毒分子的产生和清除不平衡引起的，是这些疾病的起始和进展的关键因素。在高血压的早期阶段，自由基的产生仅仅超过它们的清除，导致轻微的氧化应激。然而，这足以触发一系列下游事件，导致其他通常处于休眠状态的自由基生成系统的激活。在这些过量的水平下，自由基攻击动脉壁的细胞，导致血管功能障碍并最终导致心血管疾病。血管壁中自由基的主要来源是一种称为NADPH氧化酶的酶家族。我们的假设是，在高血压的早期阶段，这些酶中的一种的上调是许多下游效应的最初触发因素，这些下游效应最终导致心血管疾病。我们的团队是唯一准备测试这一假设的实验室，因为我们是世界上唯一一个可以获得三种不同转基因小鼠的实验室，每种小鼠都缺乏NADPH氧化酶的三种已知亚型之一。识别参与血管中自由基产生的NADPH氧化酶的特定亚型是开发阻断血管自由基产生的药物的关键第一步，从而消除高血压和主要心血管事件之间的分子联系。

Hypertension (high blood pressure) is a major risk factor for cardiovascular diseases such as heart attacks, heart failure and stroke - the major causes of death world-wide and a huge burden on the Australian health care budget. Oxidative stress, resulting from an imbalance in the production and removal of toxic molecules called free radicals within the blood vessel wall, is a key player in the initiation and progression of these disorders. In the early stages of hypertension, production of free radicals only just outweighs their removal, resulting in a mild oxidative stress. However, this is enough to trigger a cascade of downstream events leading to activation of other, normally dormant, free radical generating systems. At these excessive levels, free radicals attack the cells of the artery wall leading to blood vessel dysfunction and ultimately cardiovascular disease. A major source of free radicals in the blood vessel wall are a family of enzymes called NADPH oxidases. It is our hypothesis that upregulation of onr of these enzymes in the early stages of hypertension is the initial trigger for many of the downstream effects that ultimately lead to cardiovascular disease. Our group is uniquely poised to test this hypothesis as we are the only laboratory in the world with access to three different strains of genetically modified mice, each lacking one of the three known isoforms of NADPH oxidase. Identification of the specific isoform of NADPH oxidase involved in free radical production in blood vessels is a critical first step in developing drugs that block vascular free radical production and so remove the molecular link between hypertension and major cardiovascular events.