# Nitro-fatty acids as anti-inflammatory and anti-oxidant therapy for PAH

> **NIH NIH P01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $508,625

## Abstract

Cell signaling actions mediated by reduction-oxidation (redox)-dependent post-translational modifications
include oxidation, glutathionylation, S-nitrosation, and alkylation reactions. These reactions intimately link
metabolic and inflammatory status with changes in cell and organ function, since many enzymes, receptors
and transcriptional regulatory proteins mediating metabolic and inflammatory responses contain functionally-
significant hyperreactive Cys moieties. We now know that nitrite (NO2-) and nitrate (NO3-) are metabolized by
commensal bacteria, metalloproteins, and digestive processes, yielding nitric oxide (NO) and secondary
nitrogen oxides that elicit unique redox signaling responses via nitrosation, nitration and oxidation reactions.
The nature and amounts of various nitrogen oxides are dependent on inflammatory status, diet, acidic
microenvironments and NO3--reducing enterosalivary bacterial populations. Many of these products are
chemically reactive and generate protein NO-heme complexes, protein Cys-NO adducts (RSNO), and
electrophilic fatty acid nitroalkenes (NO2-FA) that readily and reversibly alkylate susceptible protein thiols. The
cGMP-independent pleiotropic signaling actions of NO2-FAs induce adaptive tissue responses that include
beneficial shifts in adipokine and cytokine expression, restoration of insulin sensitivity and the attenuation of
right ventricular end systolic pressure (RVESP). This motivated us to hypothesize that the promotion of nitro-
fatty acid signaling alleviates metabolic syndrome-induced hypertension and its pulmonary
complications. To test this concept, a de-risked new drug strategy is evaluated by pursuing two
mechanistically-revealing model system and clinically-based specific aims: 1. Define the molecular targets,
biochemical responses and physiological actions of a) the dietary NO2-FA precursors (NO2-, NO3-,
conjugated linoleic acid) and b) pure NO2-FA in rodent models of obesity-induced pulmonary
hypertension. 2. Evaluate the clinical responses of Group 1 pulmonary arterial hypertension patients to
the orally administered NO2-FA, 10-nitro-octadec-9-enoic acid (NO2-OA). Preliminary studies reveal that
NO2-FA-mediated PTMs will promote salutary responses, as NO2-FA have already undergone extensive
preclinical toxicology and pharmacokinetics evaluation and are in FDA-approved Phase 1 testing of both IV
and oral formulations in humans. The pulmonary vascular responses to NO2-FA are anticipated to be more
efficacious than many single-target drugs, because of the pleiotropic signaling actions of NO2-FA.

## Key facts

- **NIH application ID:** 9939666
- **Project number:** 5P01HL103455-10
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Bruce Alan Freeman
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $508,625
- **Award type:** 5
- **Project period:** 2011-06-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9939666

## Citation

> US National Institutes of Health, RePORTER application 9939666, Nitro-fatty acids as anti-inflammatory and anti-oxidant therapy for PAH (5P01HL103455-10). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9939666. Licensed CC0.

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