# PKG Signaling and Sepsis Induced ALI

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2020 · $450,487

## Abstract

An important function of the endothelium lining the inner surface of blood vessels is to provide a selective
barrier between blood and the surrounding tissues. During the development of sepsis-induced acute lung injury
(ALI) the pulmonary vascular endothelial barrier is disrupted, leading to increased permeability and massive
leakage of protein rich fluids into alveoli leading to acute respiratory distress syndrome (ARDS). In ALI, the
increased generation of reactive nitrogen species (RNS) is involved in the disruption of the endothelial barrier.
The role of the RNS, nitric oxide (NO) in regulating the endothelial barrier is complex. NO-cGMP signaling
maintains the endothelial barrier under physiologic conditions, while the injurious effects of NO can be
attributed to its reaction with superoxide to generate peroxynitrite. We have pioneered studies demonstrating
the important role played by peroxynitrite, and protein nitration, in the development of sepsis-mediated ALI
mediated via the activation of the barrier disruptive protein, RhoA. We have also recently shown that the
nitration of protein kinase G-Iα (PKG-Iα) at tyrosine (Y) 247 attenuates its enzymatic activity. PKG-Iα protects
the endothelial barrier against injury via the activation of cAMP-PKA signaling and the suppression of RhoA
signaling but through unresolved mechanisms. We have identified an inhibitory phosphorylation site on
phosphodiesterase 3A (PDE3A, a major cAMP-degrading system in the lung endothelium) that is PKG-Iα
dependent. Thus, our data implicate PKG-Iα as a critical regulator of endothelial barrier function in the lung.
Based on these findings this proposal will test the overall hypothesis that peroxynitrite exerts direct effects on
PKG-Iα activity as well as indirect effects mediated, at least in part, via PDE3A-cAMP-PKA and the
downstream modulation of RhoA and Rac1 signaling. We will also determine if preventing PKG-Iα nitration is
barrier protective in vitro and reduces lung injury in pre-clinical ARDS mouse models. We will also carry out
genetic investigations to evaluate the influence of PDE3A non-synonymous coding small nucleotide
polymorphisms (SNPs) in the development of ARDS in humans. We anticipate this proposal, using state-of-
the-art cellular, molecular, biochemical, biophysical, genetic, and whole animal approaches will increase our
understanding of the mechanisms by which interactions between PKG-Iα and PKA regulate pulmonary
endothelial barrier function under both physiologic and pathologic conditions. Further, our studies should
facilitate the development of new strategies and targets for the treatment of ALI/ARDS, a disease that still has
a mortality rate of >30%.

## Key facts

- **NIH application ID:** 9948742
- **Project number:** 5R01HL142212-03
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Stephen M Black
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $450,487
- **Award type:** 5
- **Project period:** 2018-08-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948742

## Citation

> US National Institutes of Health, RePORTER application 9948742, PKG Signaling and Sepsis Induced ALI (5R01HL142212-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9948742. Licensed CC0.

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