# Reactive Oxygen Species and Respiratory Muscle Dysfunction in Heart Failure

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2023 · $39,030

## Abstract

Abstract
 Diaphragm weakness is a significant health problem in patients with chronic heart failure and reduced
ejection fraction (CHF) because it compromises ventilation and airway clearance and contributes to cardiac
arrhythmias, peripheral vasoconstriction, and limb muscle fatigue. A mismatch in production and scavenging of
reactive oxygen species (ROS), accompanied by oxidative modifications of myofibrillar proteins, is a critical
determinant of loss of specific force (i.e., contractile dysfunction) in CHF. In this proposal, our goal is to identify
the mechanisms which are causative in diaphragm redox imbalance and ROS-mediated contractile dysfunction
in CHF. Based on our data collected during the previous funding cycle and preliminary studies, coupled with
knowledge from the existing literature, we propose three specific aims to achievel our goal. In Aim 1, we will
determine whether downregulation of a transcription factor, which is known to regulate several redox genes, in
the diaphragm is sufficient and required for excess ROS and weakness in CHF. In Aim 2, we will define the
role and mechanisms of protein oxidation on diaphragm weakness in CHF. Our preliminary data suggests that
overexpression of enzymes that reverse oxidation of specific thiol groups prevents CHF-induced contractile
dysfunction. We will expand on these studies to define the protective effects of these enzymes in CHF-induced
diaphragm weakness and the cellular and molecular mechanisms involved in this process. Aim 3 will test
oxidation of diaphragm α-actin (skeletal) as an essential molecular event in CHF-induced contractile
dysfunction. Actin is particularly relevant because it contains amino acid residues that are highly sensitive to
oxidation in regions critical for protein structure and function. We will use viral-mediated plasmid transduction
to elicit overexpression and knockdown of the relevant genes. The general main dependent variables are
diaphragm contractile properties in intact bundles and permeabilized single fibers, muscle ultrastructre, RNA-
Sequencing, ROS emission and markers of redox balance, and methionine redox proteomics. The aims and
experiments in our proposal will build an in-depth understanding of respiratory muscle biology, redox-mediated
contractile dysfunction, and identify novel mechanisms and targets to treat diaphragm weakness in CHF.

## Key facts

- **NIH application ID:** 10643945
- **Project number:** 5R01HL130318-07
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Leonardo Ferreira
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $39,030
- **Award type:** 5
- **Project period:** 2016-01-15 → 2023-08-12

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10643945

## Citation

> US National Institutes of Health, RePORTER application 10643945, Reactive Oxygen Species and Respiratory Muscle Dysfunction in Heart Failure (5R01HL130318-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10643945. Licensed CC0.

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