# Novel specialized pro-resolving lipid mediators in resolution of aortic aneurysms and rupture

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2021 · $56,652

## Abstract

PROJECT SUMMARY
Abdominal aortic aneurysms (AAA) formation and subsequent aortic rupture can lead to sudden death and is a
significant clinical problem with no currently known medical treatments available. Our recent studies have
characterized a protective role of specialized pro-resolving mediators (SPMs) that are ω-3-derived lipid
derivatives i.e. Resolvin (Rv)D1 that effectively attenuates AAA formation via modulating the M1/M2
macrophage polarization. In this proposal, we will delineate the phenotype and mechanisms of bioactive
isoforms of SPMs i.e. Resolvins (RvD1), Maresins (MaR-1), Protectins (PD-1) and Lipoxins (LxB4) that
can lead to resolution of aortic aneurysm formation and prevent aortic rupture. First, we will measure SPMs in
human AAA patients and aortic tissue from murine experimental AAA model via electrospray tandem mass
spectrometry coupled to liquid chromatography (LC/ESI-MS/MS), which is a sensitive analytical methodology
for the qualitative and quantitative analysis of lipid mediators. Then, we will the characterize the synergistic
response of these SPM bioactive isoforms in our murine AAA and aortic rupture models. Finally, we will
delineate the specific mechanisms of the bioactive isoforms of SPMs i.e. RvD1, MaR-1, PD-1 and LxB4 using
in vivo and in vitro studies. Our preliminary data demonstrates that treatment with MaR-1 can prevent the
progression of aneurysm formation that is associated with aortic smooth muscle cell-TGF-β1 signaling. Recent
reports suggest that oxidized mitochondrial (mt) DNA acts as a damage associated pattern molecule to form
NETs, but it remains to be characterized in AAAs. Therefore, the role of MaR-1 in promoting macrophage-
dependent efferocytosis (the process of uptake of apoptotic/necrotic neutrophils) associated with NET
formation will also be elucidated in human AAA tissue as well as experimental murine models. Moreover, we
will quantify SPM-related G-protein coupled receptors (GPCR) i.e. (ALX/FPR2, GPR32, GPR18, and
ChemR23) signaling in AAA. Specifically, RvD1/FPR2 signaling via AMP-activated protein kinase (AMPK) to
regulate pro-inflammatory macrophage secretion of GM-CSF and HMGB1 will be deciphered in AAA formation.
Therefore, we will characterize the unique ability of SPMs to treat preformed aneurysms and prevent
aortic rupture by modulating RvD1-FPR2 signaling, mtDNA-dependent NETosis, promoting
efferocytosis and modulating SMC-dependent TGF-β1 signaling. This multi-faceted targeted approach of
specific SPM isoforms demonstrate a clinically applicable therapeutic strategy for treatment of chronic aortic
inflammation and vascular remodeling by targeting macrophages, neutrophils and smooth muscle cells. Our
scientific premise is to perform an in-depth analysis of the roles of these pro-resolving lipid derived mediators
in the chronic models of aneurysm formation. Importantly, we will test the rigor and reproducibility of these
animal studies to determine whether these transitions occur ...

## Key facts

- **NIH application ID:** 10440978
- **Project number:** 3R01HL153341-02S1
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Ashish Kumar Sharma
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $56,652
- **Award type:** 3
- **Project period:** 2020-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10440978

## Citation

> US National Institutes of Health, RePORTER application 10440978, Novel specialized pro-resolving lipid mediators in resolution of aortic aneurysms and rupture (3R01HL153341-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10440978. Licensed CC0.

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