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

Award Number: R01HL153120
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/20/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $528,372 )
2025	2025	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cardiovascular Diseases Research	000	5	3/21/2025	NON-COMPETING CONTINUATION	$528,372
														Subtotal = $528,372

Issue Date FY: 2024 ( Subtotal = $658,711 )
2024	2024	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cardiovascular Diseases Research	000	4	3/21/2024	NON-COMPETING CONTINUATION	$604,939
2024	2024	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cardiovascular Diseases Research	001	4	6/22/2024	NON-COMPETING CONTINUATION	$53,772
														Subtotal = $658,711

Issue Date FY: 2023 ( Subtotal = $575,575 )
2023	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cardiovascular Diseases Research	000	3	3/13/2023	NON-COMPETING CONTINUATION	$575,575
														Subtotal = $575,575

Issue Date FY: 2022 ( Subtotal = $698,411 )
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cardiovascular Diseases Research	000	2	4/28/2022	NON-COMPETING CONTINUATION	$698,411
														Subtotal = $698,411

Issue Date FY: 2021 ( Subtotal = $704,821 )
2021	2021	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cardiovascular Diseases Research	000	1	4/20/2021	NEW	$634,338
2021	2021	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cardiovascular Diseases Research	001	1	6/23/2021	NEW	$70,483
														Subtotal = $704,821

Grand Total All Awards = $3,165,890

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

Award Number: R01HL153120

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/20/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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