# Matrix Metalloprotease-PAR1 Regulation of Atherosclerosis

> **NIH NIH R01** · TUFTS MEDICAL CENTER · 2020 · $709,682

## Abstract

Project Summary
Emerging evidence suggests that inappropriate matrix metalloprotease (MMP) activity may underlie the
pathogenesis of atherosclerosis and vascular inflammation. Despite data that MMPs contribute to
atherosclerotic lesion remodeling and poor outcomes, essentially nothing is known regarding the role of MMPs
as active signaling molecules in controlling the behavior of vascular cells in the context of atherosclerotic
disease. We recently made the unanticipated discovery that MMP-1 cleaves and activates protease-activated
receptor-1 (PAR1) signaling in blood vessels. This is of major import as it was the first report of a direct
signaling function of the principal collagenase in blood vessels. Notably, we found that MMP-1 activates PAR1
by cleaving the receptor at a distinct site from the canonical thrombin cleavage site which generates a longer
tethered ligand that is biased towards a different spectrum of G protein signaling pathways. The studies in this
proposal will focus on the completely unexplored role of MMP1-PAR1 in the development of atherosclerotic
plaques. Furthermore, the involvement of PAR1 in atherosclerosis (regardless of the protease agonist) as a
chronic evolving inflammatory disease, is essentially unknown. The central hypothesis to be tested in aim 1 is
that endothelial MMP-1 first acts as an active signaling molecule via PAR1 to trigger endothelial inflammation
and monocyte entry into early plaques. In advanced lesions, MMP1 from macrophages autostimulates PAR1 to
perpetuate a chronic inflammatory and mitogenic state by secretion of MCP-1 and other mediators. We will use
both cell-based experiments, and hyperlipidemic mouse models with genetic deficiency of Mmp1a or Par1. We
will determine the requirement of MMP1a and PAR1 in mouse endothelial cells for monocyte adhesion and
transmigration under shear flow conditions in vitro using mouse heart endothelial cells isolated from of
Mmp1a-/- and Par1-/- mice, and monocytes from ApoE-/- mice after high fat diet. Aim 2 will examine the role of
the MMP1-PAR1 system on circulating monocytes in subjects with coronary artery disease and acute coronary
syndromes undergoing percutaneous coronary interventions (PCI). Monocytes from patients at baseline prior
to PCI and from those being treated with a novel PAR1 pepducin, PZ-128, will be used in Parallel Plate
(arterial-shear) flow chambers to determine transmigration through endothelial monolayers. We will determine
whether subjects with a super-active Mmp1 promoter polymorphism exhibit higher expression of MMP1 that
contributes to a `MMP1-PAR1' phenotype vs `TF-PAR1' phenotype on their monocytes. Aim 3 will use adoptive
transfer of bone marrow-derived cells from Par1-/-ApoE-/- and Mmp1a-/-ApoE-/- mice to help define the cell-
type specific pathobiology (e.g. endothelium vs leukocytes) of the MMP1-PAR1 system in atherogenesis. Our
understanding of the pathophysiologic relevance of MMP1-PAR1 signaling on endothelium and monocytes/...

## Key facts

- **NIH application ID:** 9840500
- **Project number:** 5R01HL136485-03
- **Recipient organization:** TUFTS MEDICAL CENTER
- **Principal Investigator:** ATHAN KULIOPULOS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $709,682
- **Award type:** 5
- **Project period:** 2017-12-15 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9840500

## Citation

> US National Institutes of Health, RePORTER application 9840500, Matrix Metalloprotease-PAR1 Regulation of Atherosclerosis (5R01HL136485-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9840500. Licensed CC0.

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