R01HL153120

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

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.

Wake Forest University Health Sciences

TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Winston Salem, North Carolina 27157 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Required) (PA-20-183)

Amendment Since initial award the total obligations have increased 408% from $634,338 to $3,224,599.