# S-nitrosation in cell survival and cell death

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $409,375

## Abstract

PROJECT SUMMARY
Myocardial ischemia-reperfusion injury is a leading cause of death in both males and females in the United
States. Cardioprotective mechanisms hold promise for lessening this burden, but few experimental discoveries
have translated successfully into effective therapeutics. Nitric oxide, produced endogenously or administered
exogenously, has been identified as an essential component of many different cardioprotective pathways. Our
recent findings suggest that the S-nitrosation (SNO) of cysteine thiols is essential for nitric oxide-dependent
protection in female hearts, which exhibit higher baseline SNO levels compared to males and associated with
this, greater protection from ischemia-reperfusion injury. SNO levels are regulated by S-nitrosoglutathione
reductase (GSNOR), which catabolizes protein SNO, and we have evidence to suggest that GSNOR is a key
mediator of protection in the heart. We have also identified two additional targets (TRIM72, mitochondrial
proteins) that are critical for the SNO-mediated ischemic stress response in male and female hearts, but specific
mechanisms for reducing cell death and potential sex differences are not known. As such, a significant
knowledge gap exists regarding a number of fundamental questions related to the physiological and
pathophysiological role(s) of SNO signaling in male and female hearts. To address this knowledge gap, we have
developed a number of novel methods for the identification and quantitation of specific in situ SNO modification
sites in the heart. In the present application, we propose to use these methods in tandem with in vivo and ex
vivo models of myocardial ischemia-reperfusion injury and newly developed and emerging methodologies, like
in vivo stable isotope labeling by amino acids in mammals (SILAM) to assess protein turnover, quantitative mass
spectrometry, and metabolomics analysis. These approaches will be used to enhance our mechanistic
understanding of SNO signaling in sex-dependent cardioprotection through the following specific aims: 1) define
the role of TRIM72 as a protective target of SNO during ischemia-reperfusion injury, 2) define the protective role
of SNO-modified mitochondrial proteins during ischemia-reperfusion injury, and 3) define the role of GSNOR in
mitigating nitrosative stress during ischemia-reperfusion injury. If completed successfully, the aims of this
proposal will advance our mechanistic understanding of protein SNO signaling in myocardial ischemia-
reperfusion injury and cardioprotection. These studies will also provide valuable insight into how SNO-based
approaches may be targeted for the therapeutic treatment of ischemic heart disease in both males and females.

## Key facts

- **NIH application ID:** 10073347
- **Project number:** 5R01HL136496-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Mark Jeffrey Kohr
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $409,375
- **Award type:** 5
- **Project period:** 2017-12-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10073347

## Citation

> US National Institutes of Health, RePORTER application 10073347, S-nitrosation in cell survival and cell death (5R01HL136496-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10073347. Licensed CC0.

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