# Resolution of inflammation and atrial fibrillation

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2024 · $705,184

## Abstract

Systemic inflammation and oxidative stress are common in patients with AF. In atrial cardiomyocytes (CMs),
AF can be precipitated by NLRP3 inflammasome activation and IL-1β secretion. Since we have established
cardiac NLRP3 activation and IL-1β can lead to AF, we will study upstream modulators of the cardiac NLRP3
inflammasome that can be manipulated to reduce AF risk in DM.
 We have found that enzymes producing pro-inflammatory molecules are elevated and inflammation resolving
molecules are reduced in atria from humans and mice with DM. Specifically, we have found increased 12-
lipoxygenase (12-LOX, encoded by ALOX12), an enzyme that processes arachidonic acid (AA) to pro-
inflammatory metabolites in humans and mice. In humans and mice, we have found that cardiac pro-resolving
lipid mediators (SPMs) are reduced, leucine-rich repeat containing G protein-coupled receptor 6 (LGR6, encoded
by LGR6), a recently described receptor of SPMs, is downregulated, and 15-hydroxyprostaglandin
dehydrogenase (15-PGDH; encoded by HPGD), an enzyme in the inactivation of SPMs, is increased in DM atria.
Hypotheses to be tested: Since SPMs can reduce NLRP3 activation, this application explores whether DM-
associated AF risk can be mitigated by enhancing SPM signaling by reducing inflammatory lipid mediator
production (12-LOX inhibition), enhancing SPM signaling (upregulation of LGR6), or reducing SPM degradation
(downregulating of 15-PGDH).
Specific aims:
Aim 1: Determine whether inhibition of cardiac 12-LOX upregulation can reduce atrial NLRP3 activation
and AF burden in DM.
Specific Aim 2: Determine whether upregulation of cardiac LGR6 can reduce atrial NLRP3 activation and
AF burden in DM.
Specific Aim 3: Determine whether downregulation of cardiac 15-PGDH can reduce atrial NLRP3
activation and AF burden in DM.
Significance: This application explores new treatment paradigms of encouraging inflammation resolution to
prevent DM-induced AF. Using parallel experiments in humans and mice will provide mechanistic insights and
strengthen clinical relevance. A focus on prevention rather than treatment is novel and could prevent significant
morbidity associated with AF onset.

## Key facts

- **NIH application ID:** 10831082
- **Project number:** 5R01HL165704-02
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** SAMUEL C DUDLEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $705,184
- **Award type:** 5
- **Project period:** 2023-04-20 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10831082

## Citation

> US National Institutes of Health, RePORTER application 10831082, Resolution of inflammation and atrial fibrillation (5R01HL165704-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10831082. Licensed CC0.

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