# Extracellular matrix-derived chemokines mediate smoking-associated coronary atherosclerosis

> **NIH VA I01** · BIRMINGHAM VA MEDICAL CENTER · 2024 · —

## Abstract

Coronary artery disease (CAD) is a chronic inflammatory vascular condition that remains a
leading cause of death in the United States with disproportionate impact on the US veteran and
active military populations. Cigarette smoking and other tobacco products clearly accelerate the
development of CAD; however, the cellular and molecular mechanisms linking smoke with CAD
remain poorly understood. To combat these issues, our group has provided extensive evidence
linking smoke exposure with extracellular matrix degradation by matrix metalloproteases (MMPs)
and the production of bioactive peptide fragments. These bioactive matrix fragments can promote
chemotaxis (termed matrix-derived chemokines, or matrikines) and have been described by our
group and others as novel mediators of inflammation in cardiovascular disease. Despite these
observations, the contribution of matrikines to smoke-associated CAD is unknown. We provide
preliminary data demonstrating the pro-inflammatory matrikine proline-glycine-proline (PGP) and
its receptor CXC Chemokine Receptor 2 (CXCR2) to be inducible mediators of endothelial
dysfunction and vascular inflammation with smoking. We also provide evidence that neutrophil
and macrophage-derived exosomes are loaded with active proteases capable of generating PGP
in response to smoke (i.e., proteolytic exosomes). Importantly, within a local cohort of patients
with a significant history of smoking we observed that increased plasma PGP is associated with
CAD or prior coronary revascularization. These results beg the question as to whether smoke
induces a feedforward mechanism of proteolytic exosome release, PGP production, and
subsequent inflammatory cell infiltration into the vascular wall thereby accelerating the
development of CAD. For this proposal, we will build on our seminal observations by first
investigating PGP production and endothelial CXCR2 signaling as critical promoters of vascular
disease in a smoke-induced mouse model of atherosclerosis (Specific Aim 1). Secondly, we will
investigate smoke activated neutrophil and/or macrophage exosomes as direct mediators of
endothelial dysfunction and vascular inflammation (Specific Aim 2). Notably, we hypothesize that
neutrophil-exosome associated neutrophil elastase (NE) and macrophage-exosome associated
MMP-12 may propagate vascular matrix fragmentation and endothelial dysfunction in response
to smoke. Finally, we will identify PGP and NE+ / MMP-12+ exosomes as clinical biomarkers of
CAD within a cohort of subjects referred for coronary angiography and defined by their smoking
status (i.e., Never, Former, and Current, Specific Aim 3). Successful completion of these aims
will lead to an increased understanding of matrikine biology in vascular disease, as well as
improve our ability to stratify veterans at risk for smoke-induced CAD. Importantly, these studies
will likely result in the development of new biomarkers and potential new therapeutic approaches
for the prevention of CAD...

## Key facts

- **NIH application ID:** 10701357
- **Project number:** 1I01CX002495-01A2
- **Recipient organization:** BIRMINGHAM VA MEDICAL CENTER
- **Principal Investigator:** Gregory Allen Payne
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2023-10-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10701357

## Citation

> US National Institutes of Health, RePORTER application 10701357, Extracellular matrix-derived chemokines mediate smoking-associated coronary atherosclerosis (1I01CX002495-01A2). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10701357. Licensed CC0.

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