Role of Monoamine Oxidase A and Diet-Induced Monocyte Dysfunction, Macrophage Reprogramming, and Atherosclerosis

单核细胞和巨噬细胞对组织的动态平衡是必不可少的，但在代谢紊乱的背景下，它们 变得功能失调，并促进慢性炎症性疾病，包括动脉粥样硬化。然而， 潜在的机制还没有被很好地理解。我们发现，血液单核细胞慢性暴露于 西式高卡路里饮食(HCD)引起的营养应激刺激活性氧的形成 产生(ROS)并促进蛋白质硫醇氧化，导致单核细胞功能障碍和重新编程 血液单核细胞转变为促炎、促动脉粥样硬化的表型，对化学诱导剂高度敏感。 这些代谢“启动”的血液单核细胞产生重新编程和功能障碍的巨噬细胞， 对氧固醇诱导的细胞死亡敏感，有缺陷的自噬和失调的激活模式。 营养应激诱导的单核细胞活化是由H_2O_2依赖的S谷胱甘肽活化、失活和 丝裂原活化蛋白激酶磷酸酶1(MKP-1)的降解，它是两个单核细胞的主要调节因子 黏附和迁移与巨噬细胞功能和可塑性。然而，HCD诱导的过氧化氢的来源和 “预置”的血液单核细胞中的“氧化应激”尚不清楚。我们现在已经鉴定出单胺氧化酶A(MAO A)和NADPH氧化酶4(NOX4)作为营养胁迫诱导单核细胞过氧化氢的新来源，以及 巨噬细胞和作为营养应激诱导的单核细胞启动和功能障碍的媒介。我们假设 HCD刺激单核细胞产生MAO A可促进动脉粥样硬化的形成 过氧化氢的产生和MKP-1的失活，导致单核细胞启动和重新编程； 导致功能障碍、高炎症和促动脉粥样硬化的单核细胞来源的巨噬细胞 炎症分解能力受损。此外，我们建议通过使硫醇失活 转移酶谷氧还蛋白1(Grx1)和破坏硫醇氧化还原动态平衡，MAO A衍生的过氧化氢促进 诱导NOX4，放大HCD触发的氧化应激反应。来检验这些假说，并 为了阐明潜在的机制，我们提出了以下具体目标： 特定目标1：确定高热量饮食触发MAO A诱导的机制 促进单核细胞功能障碍，调节巨噬细胞的可塑性，加速动脉粥样硬化的形成。 特定目标2：确定NOX4在高热量饮食诱导的单核细胞启动中的作用， 巨噬细胞功能障碍和动脉粥样硬化形成。 具体目标3：确定高热量饮食触发单核细胞的分子机制 新陈代谢健康受试者的启动和重编程以及是否和程度 这些机制与老鼠不同。

Monocytes and macrophages are essential for tissue homeostasis, but in the context of metabolic disorders they become dysfunctional and promote chronic inflammatory diseases, including atherosclerosis. However, the underlying mechanisms are not well-understood. We showed that chronic exposure of blood monocytes to nutrient stress induced by a “Western”-style high-calorie diet (HCD) stimulates the formation of reactive oxygen species (ROS) and promotes protein thiol oxidation, resulting in monocyte dysfunction and the reprogramming of blood monocytes into a pro-inflammatory, pro-atherogenic phenotype, hyper-sensitive to chemoattractants. These metabolically “primed” blood monocytes give rise to reprogrammed and dysfunctional macrophages, sensitive to oxysterol-induced cell death, with defective autophagy and dysregulated activation profiles. Monocyte priming by nutrient stress is mediated by the H2O2-dependent S-glutathionylation, inactivation and degradation of mitogen-activated protein kinase phosphatase 1 (MKP-1), a master regulator of both monocyte adhesion and migration and macrophage function and plasticity. However, the source of HCD-induced H2O2 and “oxidative stress” in “primed” blood monocytes is not known. We have now identified monoamine oxidase A (Mao A) and NADPH oxidase 4 (Nox4) as novel sources of H2O2 induced by nutrient stress in monocytes and macrophages and as mediators of nutrient stress-induced monocyte priming and dysfunction. We hypothesize that the induction of Mao A in monocytes in response to a HCD accelerates atherogenesis by promoting H2O2 production and the inactivation of MKP-1, resulting in monocyte priming and reprogramming, and giving rise to dysfunctional, hyper-inflammatory and pro-atherogenic monocyte-derived macrophages with impaired inflammation resolving capabilities. Furthermore, we propose that by inactivating the thiol transferase glutaredoxin 1 (Grx1) and disrupting thiol redox homeostasis, Mao A-derived H2O2 promotes the induction of Nox4, amplifying the oxidative stress response triggered by HCD. To test these hypotheses and to elucidate the underlying mechanisms, we propose the following Specific Aims: Specific Aim 1: Determine the mechanisms by which high-calorie diet-triggered induction of Mao A promotes monocyte dysfunction, dysregulates macrophage plasticity, and accelerates atherogenesis. Specific Aim 2: Determine the contribution of Nox4 to high-calorie diet-induced monocyte priming, macrophage dysfunction, and atherogenesis. Specific Aim 3: Determine the molecular mechanisms by which high-calorie diets trigger monocyte priming and reprogramming in metabolically healthy human subjects and whether and to what extent these mechanisms differ from mice.