# A Role of Isolevuglandin Adducts in Essential Hypertension and Systemic Lupus Erythematosus

> **NIH NIH K08** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $158,436

## Abstract

PROJECT SUMMARY
Essential hypertension and systemic lupus erythematosus (SLE) are devastating conditions. 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, 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 in the presentation of isoLG-adducted autoantigens, the development of hypertension, and
aortic inflammation in a mouse model of essential hypertension. Moreover, in a mouse model of SLE, I have also
discovered that treatment of mice 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, isoLG adducts are processed and displayed by an
immunoproteasome dependent mechanism. 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 antigen presentation and hypertension. 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 specific populations of antigen presenting cells. IsoLG-adduct
levels will be compared with clinical parameters to determine the characteristics 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 antigen presenting cell specific LMP7 deficient animal. These animals will be studied for
the development of hypertension and inflammation in the setting of two well established acquired models of
essential hypertension in mice. Together, these studies hold the pr...

## Key facts

- **NIH application ID:** 10222781
- **Project number:** 5K08HL153789-02
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** David Patrick
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $158,436
- **Award type:** 5
- **Project period:** 2020-08-01 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10222781

## Citation

> US National Institutes of Health, RePORTER application 10222781, A Role of Isolevuglandin Adducts in Essential Hypertension and Systemic Lupus Erythematosus (5K08HL153789-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10222781. Licensed CC0.

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