# Nitric Oxide and sex differences in cardiac repair

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2020 · $383,750

## Abstract

Project Summary: This program will have a major impact in the treatment of cardiovascular disease (CVD),
the leading cause of death in men and women globally. Premenopausal women are less susceptible to heart
disease than men, and this protection is lost after menopause. Emerging data suggest that the interplay
between nitric oxide (NO) and reactive oxygen species (ROS), the nitroso-redox balance, plays a critical role in
this sex-related cardioprotection. Elucidating the mechanisms underlying these gender differences is critical for
development of effective therapies. S-nitrosylation (S-NO) of cysteine thiols is a major signaling pathway
through which NO exerts its broad regulatory actions. It is increasingly appreciated that the underlying
signaling fate of NO ultimately depends upon an intracellular state of nitroso-redox balance; such that
excessive production of ROS can disrupt physiological S-NO and that CVD may reflect dysregulated protein S-
NO. We have shown that the nitroso/redox balance is an important regulator of CV health and disease. Female
mice have 65% more S-nitrosylated proteins in the heart6 and physiologically regulate this elevated level of S-
NO with increased activity of S-nitrosoglutathione (GSNO) reductase (GSNOR), an enzyme that promotes
protein denitrosylation. We previously showed that male mice lacking S-nitrosoglutathione (GSNO) reductase,
an enzyme that governs S-NO levels by promoting protein denitrosylation (GSNOR−⁄− mice) exhibit improved
survival after myocardial infarction (MI). Furthermore, pregnant GSNOR−/− mice exhibit all of the clinical
features of a major complication in pregnancy, preeclampsia (PE), including maternal hypertension, proteinuria
and abnormal CV adaptation. Poor outcome in the GSNOR−/− females may be due to oxidative stress, as our
preliminary data shows that cardiomyocytes (CMs) from GSNOR−/− females generate more ROS as compared
to CMs from control females and GSNOR−/− males. Therefore, the state of increased S-NO can lead to an
adverse milieu if accompanied by oxidative stress and we have uncovered a sex-associated relationship
between cardiac pathology and intra-cellular nitroso-redox imbalance, which is dependent on NO and ROS
production and S-NO formation and denitrosylation. Our central hypothesis is that the absence of GSNOR
produces a sex-specific, antioxidant milieu in the setting of normal ROS levels (i.e., males) but one of
nitrosative/oxidative stress when ROS is elevated (i.e., females). Our proposal aims to identify the fundamental
mechanisms underlying this dichotomy. The specific aims are to test the hypotheses that 1) differences in
nitroso-redox protein signaling determine sex-specific responses to CV stress; 2) nitroso-redox imbalance in
cadiomyocytes during pregnancy underlies pregnancy-related CVD; and 3) GSNOR produces sex-specific
changes in the S-nitrosylation of proteins that alter CV function. Together these aims will provide novel insights
into nitroso-redox reg...

## Key facts

- **NIH application ID:** 9857640
- **Project number:** 5R01HL137355-04
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Joshua M Hare
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $383,750
- **Award type:** 5
- **Project period:** 2017-03-17 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9857640

## Citation

> US National Institutes of Health, RePORTER application 9857640, Nitric Oxide and sex differences in cardiac repair (5R01HL137355-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9857640. Licensed CC0.

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