Myeloperoxidase, Oxidant Stress and Atherogenesis

髓过氧化物酶、氧化应激和动脉粥样硬化

• 批准号: 6722794
• 负责人: Stanley L Hazen
• 金额: $ 12.75万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6722794
• 关键词: aldehydes; atherosclerosis; biomarker; cellular pathology; clinical research; coronary disorder; cytotoxicity; enzyme mechanism; gas chromatography mass spectrometry; gene targeting; genetically modified animals; human tissue; hydrogen peroxide; inflammation; laboratory mouse; low density lipoprotein; macrophage; monocyte; myeloperoxidase; oxidative stress; pathologic process; single nucleotide polymorphism; superoxides; urinalysis

DESCRIPTION (provided by applicant): This application is a competitive renewal for RO1 HL62526: "Myeloperoxidase, Oxidant Stress and Atherogenesis." Four years ago we hypothesized that monocytes use myeloperoxidase (MPO) to generate species that contribute to oxidative stress, cellular injury and conversion of LDL into an atherogenic form. During the conduct of this research we demonstrated mechanisms of how leukocyte MPO may participate in host defenses, inflammatory injury, and atherosclerosis. Despite the many links between MPO, oxidant stress, and coronary artery disease (CAD), many critical questions remain. For example, direct demonstration of a causal role for the enzyme in disease development and progression remains to be established. Further, the role of oxidation in atherogenesis has recently been questioned based upon the failure of multiple "antioxidant" trials. The present proposal is both an extension of our earlier research, and a direct effort to address these questions. It is predicated upon the hypothesis that MPO and oxidative stress are mechanistically linked to the development of cardiovascular disease. It integrates studies on basic mechanisms with a search for specific reaction products that reveal whether relevant pathways operate in human disease, and in animal models of inflammation. In preliminary studies we present evidence for a novel catalytic activity for MPO which may enable the enzyme to participate in endothelial dysfunction in CAD. We demonstrate pathways through which MPO catalysis leads to formation of reactive aldehydic intermediates that are cytotoxic and implicated in atherogenesis. We demonstrate that MPO and systemic measures of its activity are linked to atherosclerotic risk and oxidant stress in vivo. The overall goals of this proposal are to: (i) provide mechanistic insights into novel pathways of MPO catalysis and function; (ii) test the hypothesis that MPO generates cytotoxic aldehydes that promote cellular injury and oxidant stress in vivo; and (iii) use a combination of genetic and biochemical approaches to define the role of MPO and specific oxidation pathways in development of cardiovascular disease in humans.

描述（由申请人提供）：此应用是RO1 HL62526的竞争更新：“骨髓氧化酶，氧化剂应激和动脉粥样硬化。”四年前，我们假设单核细胞使用髓过氧化物酶（MPO）产生有助于氧化应激，细胞损伤和LDL转化为动脉粥样硬化形式的物种。在这项研究的进行过程中，我们证明了白细胞MPO如何参与宿主防御，炎症性损伤和动脉粥样硬化的机制。尽管MPO，氧化剂应激和冠状动脉疾病（CAD）之间存在许多联系，但仍有许多关键问题。例如，直接证明该酶在疾病发展和进展中的因果作用仍有待确定。此外，最近，基于多个“抗氧化剂”试验的失败，氧化在动脉粥样硬化中的作用已受到质疑。本提案既是我们较早的研究的扩展，又是解决这些问题的直接努力。这是基于以下假设：MPO和氧化应激与心血管疾病的发展有关。它将对基本机制的研究与搜索特定反应产品的搜索相结合，这些反应产物揭示了相关途径是否在人类疾病中起作用以及在炎症的动物模型中。在初步研究中，我们为MPO的新型催化活性提供了证据，该催化活性可能使酶可以参与CAD中的内皮功能障碍。我们展示了MPO催化导致细胞毒性并与动脉粥样硬化有关的反应性醛中间体形成的途径。我们证明了其活性的MPO和全身度量与动脉粥样硬化的风险和体内氧化剂应激有关。该提案的总体目标是：（i）提供有关MPO催化和功能新途径的机械见解； （ii）检验了MPO产生细胞毒性醛的假设，该醛在体内促进细胞损伤和氧化剂应激； （iii）使用遗传和生化方法的组合来定义MPO和特定氧化途径在人类心血管疾病发展中的作用。

项目成果

Myeloperoxidase and plasminogen activator inhibitor 1 play a central role in ventricular remodeling after myocardial infarction.

• DOI: 10.1084/jem.20021426
• 发表时间: 2003-03-03
• 期刊: JOURNAL OF EXPERIMENTAL MEDICINE
• 影响因子: 15.3
• 作者: Askari, AT;Brennan, ML;Zhou, XR;Drinko, J;Morehead, A;Thomas, JD;Topol, EJ;Hazen, SL;Penn, MS
• 通讯作者: Penn, MS

Hypercapnia-induced activation of brainstem GABAergic neurons during early development.

高碳酸血症诱导早期发育过程中脑干 GABA 能神经元的激活。

• DOI: 10.1016/s1569-9048(03)00041-7
• 发表时间: 2003
• 期刊: Respiratory physiology & neurobiology
• 影响因子: 2.3
• 作者: Zhang,L;Wilson,CG;Liu,S;Haxhiu,MA;Martin,RJ
• 通讯作者: Martin,RJ

Apolipoprotein A-I is a selective target for myeloperoxidase-catalyzed oxidation and functional impairment in subjects with cardiovascular disease.

• DOI: 10.1172/jci21109
• 发表时间: 2004-08
• 期刊: The Journal of clinical investigation
• 作者: Lemin Zheng;Benedicta N. Nukuna;M. Brennan;Mingjiang Sun;M. Goormastic;Megan Settle;D. Schmitt