# Novel mechanisms of the thrombotic complications of atherosclerosis

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $420,956

## Abstract

Current clinical and pathological data suggest an ongoing major shift in the mechanisms of the
thrombotic complications of human atherosclerosis. Human plaques contain less lipid and fewer
macrophages in the statin era. Patients with acute coronary syndromes (ACS) include more and younger
women, and obese and insulin resistant individuals. ST segment elevation myocardial infarctions (STEMIs)
have declined as non-STEMIs have risen. We have marshaled evidence for a shift in the mechanisms of ACS.
In the current era of intense LDL lowering, rupture of so-called “vulnerable plaques” now causes fewer
acute coronary syndromes while superficial erosion is increasing as a proportion of ACS. While we
have considerable mastery of the biological basis of plaque rupture, and the mechanisms by which lipid-
lowering can attenuate this trigger of thrombosis, a striking knowledge gap yawns regarding mechanisms
of superficial erosion. This process differs substantially from plaque rupture: human lesions that have
provoked erosion generally lack a prominent lipid collection, have few macrophages and more proteoglycan
and glycosaminoglycans (GAGs) rather than thin, collagen-poor fibrous caps. Recent clinical data suggest that
the management ACS due to erosion, unlike those due to plaque rupture, does not require urgent invasive
treatment, rendering the quest for greater understanding of the mechanisms of erosion medically imperative.
Our newly published data suggest a role for neutrophils (polymorphonuclear leukocytes, PMN), and neutrophil
extracellular traps (NETs) in superficial erosion. We will use a validated experimental preparation in mice that
superimposes disturbed flow on a GAG and proteoglycan-rich intima, conditions that pertain to human plaques
complicated by superficial erosion, to probe molecular and cellular mechanisms of this type of thrombotic
complication of atherosclerosis. My proposal centers on the unified theme of PMN and NET functions. 1) We
will test using mice deficient in peptidyl arginine deiminase 4 (PAD4) the hypothesis that at sites of flow
disturbance in arteries with erosion-like intimas, NETs participate critically in local endothelial injury and
thrombosis. 2) We will test the hypothesis that myeloid-related protein (MRP) 8/14, we have previously
implicated in arterial diseases, contributes to local NETosis and in endothelial injury and thrombosis at sites of
flow disturbance in arteries with erosion-like intimas. 3) We test the hypothesis that mice bearing in myeloid
cells the V617F Jak2 variant associated with clonal hematopoiesis and increased atherosclerotic risk in
humans, will have aggravated NETosis and endothelial injury and thrombosis at sites of flow disturbance in
arteries with erosion-like intimas. This aim will not only provide mechanistic information regarding superficial
erosion, but will help elucidate the mechanism of increased thrombotic events in individuals who bear this
somatic mutation common in those with clo...

## Key facts

- **NIH application ID:** 10428552
- **Project number:** 5R01HL134892-04
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Peter Libby
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $420,956
- **Award type:** 5
- **Project period:** 2019-07-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10428552

## Citation

> US National Institutes of Health, RePORTER application 10428552, Novel mechanisms of the thrombotic complications of atherosclerosis (5R01HL134892-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10428552. Licensed CC0.

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