# Stress-induced trained immunity in cardiovascular disease

> **NIH NIH P01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $505,804

## Abstract

PROJECT SUMMARY
 In the last decade, emerging evidence has unveiled that the innate immune system retains long-
term epigenetic and metabolic changes after infection or vaccination. This de facto innate immune memory
has been termed ‘trained immunity’ and is characterized by myeloid cells’ hyper-responsiveness following
a subsequent stimulus. Recent work has shown that sterile atherogenic/inflammatory triggers, such as
oxidized LDL or catecholamines, similarly induce a trained immunity phenotype through epigenetic and
metabolic reprogramming of the myeloid compartment. The long-term persistence of trained immunity in
vivo is due to the reprogramming of hematopoietic stem and progenitor cells (HSPC) in the bone marrow.
 We have recently reported that monocytes isolated from patients with risk factors for CVD, such as
familial hypercholesterolemia or pheochromocytoma, display a ‘trained’ phenotype. Importantly, in patients
with established coronary artery disease, we found HSPCs reprogrammed towards a pro-inflammatory
myeloid lineage. Project 2 will focus on stress-induced trained immunity’s mechanistic aspects in
cardiovascular disease patients and mouse models. Our central hypothesis is that chronic stress induces
trained immunity via HSPC reprogramming, which exacerbates the development of atherosclerosis and
worsens the outcome of cardiovascular events.
 In Aim 1, we will use deep phenotyping and imaging to study patients at high risk for cardiovascular
events in order to obtain an integrated view of stress-induced reprogramming of the myeloid cell
compartment. In Aim 2, we will study mice that were exposed to chronic mild psychosocial stress or to key
hormonal signals that promote peripheral effects on stress, followed by a rest period of 4 weeks. After the
rest period, stressed cohorts and non-stressed controls will undergo coronary artery ligation or induction of
atherosclerosis to test the hypothesis that preceding stress or exposure to stress hormones activates
trained immunity, thus increasing myelopoiesis and consequently worsening cardiovascular disease.
 Our unique ability to profile patients’ HSPCs at Radboudumc, the human models, and the mouse
models that mimic them will yield critical insights into the relationship between cardiovascular disease and
psychosocial stress.

## Key facts

- **NIH application ID:** 10891374
- **Project number:** 5P01HL131478-07
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Willem Mulder
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $505,804
- **Award type:** 5
- **Project period:** 2017-03-17 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10891374

## Citation

> US National Institutes of Health, RePORTER application 10891374, Stress-induced trained immunity in cardiovascular disease (5P01HL131478-07). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10891374. Licensed CC0.

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