Anti-atherosclerotic effects of angiotensin fragments & non-AT1 receptors: Validation as innovative therapeutic targets

血管紧张素片段的抗动脉粥样硬化作用

• 批准号: nhmrc : 436823
• 负责人: Prof Grant Drummond
• 金额: $ 34.14万
• 依托单位: Monash University
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2007
• 资助国家: 澳大利亚
• 起止时间: 2007-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/anti-atherosclerotic-effects-therapeutic-targets/99904
• 关键词: Anti; atherosclerotic; effects; angiotensin; fragments

In Australia the largest cause of death is coronary heart disease (CHD) leading to heart attacks or stroke and claiming a staggering 28,000 lives a year. Atherosclerosis is one of the leading causes of cardiovascular disease, with diseased vessels not able to fully dilate and the plaque that has built up inside these vessels impeding blood flow and possibly rupturing, resulting in heart attacks and stroke. One of the major players in the development and progression of atherosclerosis is the hormone, angiotensin II. Angiotensin II has been found to trigger many factors that cause thickening of the vessel wall, inflammation and imbalances in vasodilator capacity (e.g. oxidative stress and endothelial dysfunction), all of which contribute to atherosclerosis. Clinical trials with drugs that inhibit the formation of angiotensin II (ACE inhibitors), or block the action of angiotensin II (angiotensin receptor antagonists), have demonstrated a significant decrease in mortality in patients with high risk for cardiovascular disease. However their mechanism(s) of action are not fully understood as the circulating levels of shorter fragments of angiotensin II (such as Ang IV and Ang (1-7)) are raised in the blood when these drugs are used and may contribute to the protective effects of these drugs. Importantly, we have found that both Ang IV and Ang (1-7) have protective effects in atherosclerotic blood vessels. Therefore, we hypothesise that fragments of angiotensin II (such as Ang IV and others) exert anti-atherogenic effects via distinct binding sites that oppose the effects caused by angiotensin II, and that these may be partly responsible for the cardio-protective effects of the ACE inhibitors and angiotensin receptor antagonists. Thus, information gained 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 the management of atherosclerosis.

在澳大利亚，最大的死亡原因是冠心病（CHD），导致心脏病发作或中风，每年夺去28，000人的生命。动脉粥样硬化是心血管疾病的主要原因之一，患病的血管不能完全扩张，在这些血管内积聚的斑块阻碍血液流动并可能破裂，导致心脏病发作和中风。血管紧张素II是动脉粥样硬化发生和发展的主要参与者之一。已经发现血管紧张素II触发许多因素，这些因素导致血管壁增厚、炎症和血管扩张能力的失衡（例如氧化应激和内皮功能障碍），所有这些都有助于动脉粥样硬化。抑制血管紧张素II（ACE抑制剂）形成或阻断血管紧张素II（血管紧张素受体拮抗剂）作用的药物的临床试验表明，心血管疾病高危患者的死亡率显著降低。然而，它们的作用机制尚未完全了解，因为当使用这些药物时，血管紧张素II的较短片段（如Ang IV和Ang（1-7））的循环水平在血液中升高，并且可能有助于这些药物的保护作用。重要的是，我们已经发现Ang IV和Ang（1-7）在动脉粥样硬化血管中具有保护作用。因此，我们假设血管紧张素II片段（如Ang IV等）通过不同的结合位点发挥抗动脉粥样硬化作用，这些结合位点对抗血管紧张素II引起的作用，并且这些可能是ACE抑制剂和血管紧张素受体拮抗剂的心脏保护作用的部分原因。因此，在我们的研究中获得的信息将是有用的，在指导未来的处方实践中的临床管理冠心病和中风，并设计新的治疗化合物的动脉粥样硬化的管理。