# The role of protease-activated receptor 2 in atherosclerosis

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2020 · $401,250

## Abstract

ABSTRACT
Arterial thrombosis resulting from plaque disruption is a leading cause of death due to complications
arising from myocardial infarction and stroke. Previous studies demonstrate hypercholesterolemic
conditions significantly increase the risk of arterial thrombosis via modification of coagulation proteins.
These effects occur through oxidation of lipoproteins and subsequent uptake or activation by
inflammatory signaling receptors. Tissue factor (TF), the cellular activator of the clotting cascade, is
upregulated via oxidized lipoproteins induced by the inflammatory state in atherosclerotic plaques.
This allows for accumulation and concentration of TF in atherosclerotic lesions. Importantly, while TF
can create a thrombotic event via plaque rupture and exposure to blood; TF can also activate and
signal through a cell associated receptor, protease-activated receptor 2 (PAR2). Our strong
preliminary data demonstrates deficiency of PAR2 attenuates early (12 weeks) and advanced (24
weeks) atherosclerosis via non hematopoietic cells. Further, we present extensive preliminary
studies demonstrating PAR2 signaling results in vascular smooth muscle cell (VSMC)
transdifferentiation into a lipid-laden macrophage-like cell via signaling and activation of krüppel-like
factor 4 (KLF4) and human antigen R (HuR). Our central hypothesis is that PAR2 regulates VSMC-
mediated pathology in atherosclerosis. In Specific Aim 1 we will determine the molecular mechanism
of PAR2-mediated VSMC transdifferentiation via activation of KLF4 and HuR. In Specific Aim 2, we
will determine the role of VSMC-specific PAR2 deletion and pharmacologic PAR2 inhibition in a
relevant disease model of atherosclerosis. Together, our studies will increase our understanding of
how PAR2 elicits atherosclerosis and may result in a novel therapeutic target to beneficially effect
cardiovascular outcomes.

## Key facts

- **NIH application ID:** 9895849
- **Project number:** 5R01HL141404-03
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** Albert Phillip Owens III
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $401,250
- **Award type:** 5
- **Project period:** 2018-05-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9895849

## Citation

> US National Institutes of Health, RePORTER application 9895849, The role of protease-activated receptor 2 in atherosclerosis (5R01HL141404-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9895849. Licensed CC0.

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