Opposing roles of Nox 1 and Nox 4 in vascular physiology and pathophysiology

Nox 1 和 Nox 4 在血管生理学和病理生理学中的相反作用

• 批准号: 7788447
• 负责人: Kathy K Griendling
• 金额: $ 34.88万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-13 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7788447
• 关键词: Agonist; Antioxidants; Ants; Apoptosis; Arteries; Atherosclerosis; Binding; Blood Vessels; Cardiovascular Diseases; Catalytic Domain; Cell Culture Techniques; Cell Cycle; Cell Differentiation process; Cell Proliferation; Cell physiology; Cells; Data; Development; Disease; Enzymes; Family; Functional disorder; Goals; Growth; Growth Factor; Homologous Gene; Hydrogen Peroxide; Hypertension; In Vitro; Inflammation; Injury; Ischemia; Knock-out; Laboratories; Lesion; Link; Location; Mediating; Membrane; Modeling; NADPH Oxidase; NADPH Oxidase 1; Oxidation-Reduction; Oxygen; Pathogenesis; Pathology; Pharmaceutical Preparations; Phenotype; Physiological; Physiology; Platelet-Derived Growth Factor; Play; Process; Production; Proteins; Reactive Oxygen Species; Regulation; Role; Signal Transduction; Signaling Molecule; Smooth Muscle Myocytes; Source; Stimulus; Superoxides; Testing; Therapeutic; Up-Regulation; Vascular Diseases; Vascular Smooth Muscle; antioxidant therapy; atherogenesis; attenuation; base; bone morphogenic protein; cell growth; cell type; human CYBA protein; in vivo; in vivo Model; inhibitor/antagonist; insight; prevent; response; restenosis; senescence; vascular smooth muscle cell proliferation; vasoconstriction

Reactive oxygen species (ROS) have been implicated in both normal vascular function and in the pathogenesis of vascular disease. For a number of years, our laboratory has been studying the NADPH oxidase (Nox) family of enzymes, which are important sources of ROS in the vasculature. We have shown that cells in the vessel wall express multiple Nox proteins, and that these proteins are differentially regulated, produce different ratios of superoxide and hydrogen peroxide, have distinct intracellular locations, and importantly, appear to serve distinct cellular functions. Nox1 is activated by growth factors and is implicated in vascular smooth muscle proliferation, while Nox4 appears to regulate constitutive ROS production and to maintain cell differentiation. We suggest that while Noxl is activated in pathophysiological situations, Nox4 controls the "redox set point" of the cell, and is regulated by agonists that maintain the differentiated phenotype. We have intriguing new preliminary data suggesting that bone morphogenic protein-4 (BMP4) prevents platelet-derived growth factor (PDGF)-induced proliferation, potentially by activating Nox4. The overall goal of this project is thus to better define the mechanisms that differentially regulate Nox1 and Nox4 and to determine their contrasting roles in the control of cell proliferation. In Aim 1, we will define the mechanisms by which Noxl and Nox4 expression are regulated by PDGF. We hypothesize that the transcriptional mechanisms activated by PDGF include MEF2 to induce Noxl and ERK1/2-mediated activation of FoxMI to repress Nox4. Aim 2 is focused on determining the functional role of Nox4 and inhibition of Noxl in BMP-mediated attenuation of vascular smooth muscle cell proliferation. Our preliminary data show that BMP4 inhibits PDGF-induced proliferation, in part by inhibiting Noxl. BMP4 also increases H2O2 production, leading us to propose that it activates Nox4, resulting in H202-induced upregulation of the cell cycle inhibitor p21^"'. In Aim 3, we plan to determine the role of Noxl and Nox4 in collateral formation. Our model predicts that the expression and activity of Nox4 influence growth factor responsiveness, while PDGF-induced proliferation requires Noxl. In this Aim, we will test this hypothesis using a physiologically relevant stimulus; that of ischemia-induced collateral formation. Finally, in Aim 4, we will determine the role of Nox4 in neointimal formation in vivo. We hypothesize that knockout of Nox4 will reduce physiologically necessary H2O2 production and allow Noxl signaling to proceed unchecked, leading to exacerbated lesion formation after vessel injury. This combination of in vitro and in vivo studies will allow Us to gain insight into the distinct and potentially opposing roles of Noxl and Nox4 in normal vascular function and in vascular disease. These studies will provide import;ant basic information on which to base the development of new therapies that target only those aspects of oxidative signaling that contribute to pathology.

活性氧（Reactive oxygen species， ROS）在正常血管功能和血管损伤中都有作用