# Reactive Species in Vascular Disease: Mechanisms of Injury

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2021 · $440,000

## Abstract

Project Summary/Abstract
While the molecular mechanisms for the regulation of vascular tone by nitric oxide are well appreciated, the
targets of nitric oxide (NO) signaling at the proteome level are incomplete. Decline in synthesis and bioavailability
of NO is central to the pathogenesis of cardiovascular diseases and in age-dependent deterioration of vascular
function and cardiac muscle performance. However, the signaling pathways affected by the decline in
bioavailable NO during ageing remain unclear. Furthermore, several current clinical trials aim to restore the
levels of NO in humans with hopes to improve cardiovascular and skeletal muscle physiological function and
prevent vascular disease and disability in aged populations. Presently, the signaling pathways reestablished by
pharmacological restoration of NO remain unknown. Therefore, we propose to use chemoselective, high-
resolution, mass spectrometry-based proteomic technologies to identify and quantify for the first time at the organ
and cellular level the two post-translational modifications protein phosphorylation and cysteine S-nitrosation, that
constitute the two principle NO signaling pathways. We will resolve changes in the canonical signaling cascade,
activation of soluble guanylate cyclase, production of cGMP and Ser/Thr phosphorylation of proteins and the
complimentary selective S-nitrosylation of cysteine residues as a function of gender, ageing and in the setting of
NO deficiency before and after restoration of bioavailable NO. Guided by preliminary data we will also investigate
a novel mechanism for the regulation of the NAD-dependent protein deacetylase sirtuin 2 by NO. This regulatory
function may have important cardioprotective functions. Completion of the proposed aims will provide new
mechanistic insights and a framework for system-level appreciation of NO signalling in the cardiovascular
system.

## Key facts

- **NIH application ID:** 10064019
- **Project number:** 5R01HL054926-22
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** HARRY ISCHIROPOULOS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $440,000
- **Award type:** 5
- **Project period:** 1997-09-05 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10064019

## Citation

> US National Institutes of Health, RePORTER application 10064019, Reactive Species in Vascular Disease: Mechanisms of Injury (5R01HL054926-22). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10064019. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*