# A Role of Isolevuglandins in Essential Hypertension and Systemic Lupus Erythematosus

> **NIH VA IK2** · VETERANS HEALTH ADMINISTRATION · 2024 · —

## Abstract

PROJECT SUMMARY
Essential hypertension and systemic lupus erythematosus (SLE) are devastating conditions for United States
Veterans. An estimated one-third of the world’s population suffers from hypertension despite a large number of
treatment options. SLE is a heterogeneous disease the treatment of which is limited to the use of non-specific
global immunosuppression. There is a lack of understanding of the mechanisms underlying these conditions.
Isolevuglandins (IsoLGs) are oxidation products of fatty acids that form as a result of reactive oxygen species.
These molecules adduct covalently to lysine residues of proteins. Adducted proteins are then presented as
autoantigens to T-cells resulting in immune cell activation and resultant hypertension and systemic autoimmunity.
Based upon previously published studies and preliminary data, it is clear that both essential hypertension and
SLE are initiated by this process of isoLG-adduct formation, processing, and immune cell activation. I have
discovered an important role of the immunoproteasome subunit LMP7 in the presentation of isoLG-adducted
autoantigens, the development of hypertension, and aortic inflammation in a mouse model of essential
hypertension. Additionally, in a mouse model of SLE, I have also discovered that treatment with an isoLG
scavenger, 2-hydroxybenzylamine, attenuates hypertension and systemic autoimmunity. Finally, I found that a
subset of patients with SLE exhibit isoLG accumulation within antigen presenting cells, suggesting a unique
clinical profile and potential therapeutic opportunities for these patients. I hypothesize that within antigen
presenting cells in both hypertension and SLE, isoLG adducts are processed and displayed by an
immunoproteasome dependent mechanism with a primary role of the immunoproteasome subunit LMP7.
Additionally, patients with SLE that exhibit isoLG-adduct accumulation exhibit unique disease characteristics. My
specific aims are: (1) To determine a role of isoLG-adducts in SLE-associated hypertension and disease
heterogeneity. (2) To determine the role of immunoproteasome function in isoLG-adducted antigen presentation
and hypertension. (3) To determine the role of LMP7 function in immune activation, isoLG-adducted antigen
presentation, and hypertension in SLE. To accomplish these aims we will recruit SLE patients and obtain
peripheral blood mononuclear cells. Cells will be studied by flow cytometry for the presence of isoLG-adduct
accumulation within unique populations of antigen presenting cells. IsoLG-adduct levels will be compared with
clinical parameters to determine the parameters that correlate with adduct accumulation. To study the function
of the immunoproteasome, I will utilize mice globally deficient for the three subunits of the immunoproteasome
(TKO mice). I have also generated a conditional knockout of the chymotrypsin subunit of the immunoproteasome
(LMP7fl/fl) which will be crossed to CD11c-Cre transgenic animals to generate an ant...

## Key facts

- **NIH application ID:** 10726576
- **Project number:** 5IK2BX005376-03
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** David Patrick
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2021-10-01 → 2026-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10726576

## Citation

> US National Institutes of Health, RePORTER application 10726576, A Role of Isolevuglandins in Essential Hypertension and Systemic Lupus Erythematosus (5IK2BX005376-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10726576. Licensed CC0.

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