# Nitrite-signaling to modulate the metabolic syndrome and PH in patients with PH-HFpEF

> **NIH NIH P01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $630,438

## Abstract

Pulmonary arterial hypertension (PAH; WHO Group I) is a disease of the small pulmonary arteries,
characterized by vasoconstriction, vascular proliferation, and remodeling. Over the first 4 years of our
translational Program Project Grant (tPPG), we have focused on the less studied sub-phenotypes of
pulmonary hypertension, namely pulmonary venous hypertension (PVH or Group II), which typically arises in
the setting of the metabolic syndrome. Group II PVH is also referred to as pulmonary hypertension in the
setting of heart failure with preserved ejection fraction (PH-HFpEF) and is extremely common, with no currently
approved effective therapies. It has become increasingly apparent that major risk factors for the development
of both Group I disease and Group II (PH-HFpEF) include all features of the metabolic syndrome (obesity,
insulin resistance, and systemic hypertension). Importantly, both the relaxation and abnormal proliferation of
pulmonary vascular smooth muscle cells and the central mechanisms underlying the metabolic syndrome are
strongly modulated by nitric oxide (NO)-dependent reactions, inducing both cGMP-dependent vasodilation and
cGMP-independent reactions that inhibit smooth muscle cell proliferation, inflammation, and oxidative stress,
as well as improve insulin sensitivity. In Project 1 it is hypothesized that new vascular-targeted, NO-based
therapeutic strategies will enhance the treatment of PAH and metabolic syndrome, providing a new therapy for
the currently untreatable and extremely common PH-HFpEF.
To this end, we have identified two reactive nitrogen species that potently modulate both PH and the metabolic
syndrome, nitrite (NO2-) and nitro-fatty acids (NO2-FA). In our preliminary data we find that nitrite (NO2-) can be
bioactivated in skeletal muscle, via the myoglobin oxidoreductase reaction, to activate mitochondrial SIRT3-
AMPK-Glut4 signaling pathways to improve glucose homeostasis and reverse established PH-HFpEF.
Interestingly, nitrite also activates AMPK in the pulmonary vascular smooth muscle, independent of SIRT3
signaling, suggesting signaling convergence around AMPK. In addition to direct bioactivation of nitrite in
smooth and skeletal muscle, nitrite reacts with dietary linoleic acid in the acidified stomach to generate nitrated
fatty acids, which are potent electrophiles that post-translationally regulate Keap1-Nrf2 mediated antioxidant
and anti-inflammatory signaling. We have now developed novel mouse and rat models of PH-HFpEF and have
completed critical human phase 2 safety and proof of concept clinical trials of oral and inhaled nitrite therapy in
patients with PAH. For the next phase of support we plan to study the mechanisms underlying the
development of PH-HFpEF in the setting of metabolic syndrome. Fulfilling the translational directive of the
tPPG, our project extends our completed phase 1 PK and safety studies to a randomized placebo-controlled
trial of oral nitrite versus placebo for patients with PH...

## Key facts

- **NIH application ID:** 9939664
- **Project number:** 5P01HL103455-10
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Mark T Gladwin
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $630,438
- **Award type:** 5
- **Project period:** 2011-06-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9939664

## Citation

> US National Institutes of Health, RePORTER application 9939664, Nitrite-signaling to modulate the metabolic syndrome and PH in patients with PH-HFpEF (5P01HL103455-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9939664. Licensed CC0.

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