Atherosclerosis, the underlying cause of myocardial infarction and stroke, is a lipid-driven chronic inflammatory disease characterized by lipoprotein and leukocyte accumulation in the vessel wall. Among leukocytes, monocyte-derived intimal macrophages are arguably the most decisive contributors to the development, progression, exacerbation, and regression of atherosclerosis. As key effectors of inflammation, proteolysis, oxidative stress, lipid clearance, and efferocytosis, macrophages have long been therapeutic targets for the treatment of atherosclerosis. However, macrophage content in the vessel wall is highly dynamic, relying on multiple systemic and local processes that are governed by distinct biological pathways. Recently, we showed that psychosocial stress, which potentiates cardiovascular disease (CVD), aggravates atherosclerosis by disturbing the macrophage supply chain; animals subjected to intermittent psychosocial stress developed inflamed lesions containing more numerous macrophages than controls. In this project, we will ask how stress affects mechanisms related to influx of monocytes (medullary myelopoiesis, mobilization of monocytes and stem cells, extramedullary myelopoiesis, and monocyte influx to lesions), macrophage accrual in lesions (macrophage differentiation and local proliferation), and macrophage efflux (macrophage death through apoptosis, necrosis, or secondary necrosis, and macrophage emigration). Collectively, we refer to these as macrophage dynamics. We will investigate the impact of stress on macrophage dynamics in the progression and regression of atherosclerosis, with specific focus on the sympathetic nervous system and neuronal guidance cues. We will identify the decision nodes that control processes related to macrophage dynamics with the ultimate aim of targeting them therapeutically.

Public Health Relevance

Social stress is a risk factor for atherosclerotic disease. Macrophages are key cells in the progression and regression of atherosclerosis. This proposal will investigate how social stress affects macrophage dynamics in atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL131478-04
Application #
9884811
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Danthi, Narasimhan
Project Start
Project End
Budget Start
2020-03-01
Budget End
2021-02-28
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Type
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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