Nox4 and the Redox-Regulation of MKPs in Monocyte Recruitment and Atherosclerosis

Nox4 和 MKP 在单核细胞募集和动脉粥样硬化中的氧化还原调节

• 批准号: 8394001
• 负责人: Reto H.R. Asmis
• 金额: $ 47.05万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-16 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394001
• 关键词: Address; Adhesions; Arterial Fatty Streak; Atherosclerosis; CCL2 gene; Cardiovascular Diseases; Chemotactic Factors; Chemotaxis; Chronic; Cysteine; Data; Development; Dyslipidemias; Endothelium; Enzymes; Family member; Functional disorder; Hematopoietic; Hydrogen Peroxide; Hyperglycemia; Hyperlipidemia; In Vitro; Inflammatory; Link; MAP Kinase Gene; Mediating; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolic stress; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mus; NADPH Oxidase; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Phenotype; Phosphoric Monoester Hydrolases; Physiological; Post-Translational Protein Processing; Process; Protein S; Proteins; Regulation; Role; Signal Pathway; Sulfhydryl Compounds; Testing; atherogenesis; base; chemokine; glutaredoxin; injured; loss of function; macrophage; migration; monocyte; novel; overexpression; penicillamine-glutathione mixed disulfide; response

DESCRIPTION (provided by applicant): Chemokine-driven transmigration of monocytes into the subendothelial space is a fundamental and rate- limiting process in atherogenesis. Our preliminary data show that this process is dysregulated by metabolic stress and that increased monocyte responsiveness to chemokines appears to accelerate atherosclerotic plaque development. We have now uncovered a novel thiol redox-sensitive mechanism in monocytes that upon dysregulation by metabolic disorders, "primes" and transforms monocytes into a hyper-chemotactic pro- atherogenic phenotype. In addition, we have found that the recently discovered monocytic NADPH oxidase 4 is a mediator of monocyte priming. We propose that metabolic stress-induced Nox4 and the subsequent increase in H2O2 formation in monocytes promote the S-glutathionylation and inactivation of mitogen-activated protein kinase phosphatases (MPKs); MKPs are the enzymes responsible for the deactivation of both phospho-ERK and phospho-p38MAPK, the two principal MAPK pathways mediating MCP-1-induced monocyte adhesions and migration. We hypothesize that monocyte MPKs represent a novel, critical mechanistic link between oxidative stress induced by metabolic disorders and the formation of atherosclerotic lesions. Our studies support a new paradigm implicating monocyte priming and dysfunction as an early primary contributor to atherogenesis. The studies we propose here aim to test this paradigm and elucidate the underlying molecular mechanisms. Specific Aim 1: Determine the roles of mitogen-activated protein kinase phosphatases (MKP) in the redox regulation of monocyte adhesion, chemotaxis, and recruitment into atherosclerotic lesions. Specific Aim 2: Determine the roles of protein-S-glutathionylation in monocyte recruitment and the development of atherosclerotic lesions. Specific Aim 3: Determine the roles of monocytic Nox4 in monocyte priming and atherogenesis. PUBLIC HEALTH RELEVANCE: Monocyte recruitment into the vessel wall is an essential step in the development of atherosclerotic lesions - a process initiated by the injured vasculature releasing chemokines in response to inflammatory processes. With our discovery that chronic metabolic stress dramatically enhances the responsiveness of blood monocytes to chemoattractants and increases monocyte migration, we have uncovered a completely novel mechanism by which metabolic disorders promote atherosclerosis. Our data support a new paradigm that implicates monocyte priming and dysfunction induced by metabolic disorders as an early primary contributor to atherogenesis. The studies we propose here aim to test this paradigm and elucidate the underlying molecular mechanisms. Should our paradigm prove correct, our studies may have identified the molecular basis for a causal relationship that explains the well-established associations between metabolic disorders, oxidative stress, and cardiovascular diseases.

描述（由申请人提供）：趋化因子驱动的单核细胞向内皮下空间的迁移是动脉粥样硬化形成中的基本和限速过程。我们的初步数据表明，这一过程是失调的代谢应激和单核细胞对趋化因子的反应性增加似乎加速动脉粥样硬化斑块的发展。我们现在已经发现了单核细胞中的一种新的硫醇氧化还原敏感性机制，其在代谢紊乱失调时，“引发”单核细胞并将其转化为超趋化性促动脉粥样硬化表型。此外，我们发现最近发现的单核细胞NADPH氧化酶4是单核细胞启动的介质。我们提出，代谢应激诱导的Nox 4和随后的H2 O2形成的单核细胞中的增加促进S-谷胱甘肽化和有丝分裂原活化的蛋白激酶磷酸酶（MPKs）的失活; MKPs是负责磷酸化ERK和磷酸化p38 MAPK的失活的酶，这两个主要的MAPK途径介导MCP-1诱导的单核细胞粘附和迁移。我们假设单核细胞MPKs代表了代谢紊乱诱导的氧化应激和动脉粥样硬化病变形成之间的一种新的、关键的机制联系。我们的研究支持一种新的范式，即单核细胞启动和功能障碍是动脉粥样硬化形成的早期主要因素。我们在这里提出的研究旨在测试这种范式，并阐明潜在的分子机制。具体目标1：确定丝裂原活化蛋白激酶磷酸酶（MKP）在氧化还原调节单核细胞粘附、趋化性和招募到动脉粥样硬化病变中的作用。具体目标2：确定蛋白-S-谷胱甘肽化在单核细胞募集和动脉粥样硬化病变发展中的作用。具体目标3：确定单核细胞Nox 4在单核细胞引发和动脉粥样硬化形成中的作用。 公共卫生相关性：单核细胞募集到血管壁中是动脉粥样硬化病变发展的重要步骤-这是由受损的血管系统响应炎症过程释放趋化因子启动的过程。随着我们发现慢性代谢应激显著增强血液单核细胞对趋化因子的反应性并增加单核细胞迁移，我们发现了一种代谢紊乱促进动脉粥样硬化的全新机制。我们的数据支持一种新的范式，即代谢紊乱诱导的单核细胞启动和功能障碍是动脉粥样硬化形成的早期主要因素。我们在这里提出的研究旨在测试这种范式，并阐明潜在的分子机制。如果我们的范式被证明是正确的，我们的研究可能已经确定了因果关系的分子基础，解释了代谢紊乱，氧化应激和心血管疾病之间的既定联系。