Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Establishing the role of exercise in the maintenance of a cardioprotective stress response

Award Number: R01HL178616
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2030

Group Awards By:

View Award Description

Establishing the role of exercise in the maintenance of a cardioprotective stress response - The cardioprotective benefits of exercise are well-established and have been generally attributed to metabolic reprogramming and adaptive changes in cardiomyocyte (CM) function. We found that exercise also induces the Nrf2 (nuclear factor erythroid-derived 2, or Nfe2l2)-dependent antioxidant gene program in cardiac fibroblasts (CF), which may prevent fibroblast activation and the development of cardiac fibrosis. Nrf2 is a stress-responsive transcription factor that is typically targeted for ubiquitin-mediated degradation by Keap1. Intracellular oxidant production inactivates Keap1, allowing Nrf2 to accumulate and induce the expression of antioxidant genes. The cardioprotective nature of Nrf2 is supported by several studies, and a common null variant of the NRF2- dependent antioxidant gene, glutathione S-transferase mu 1 (GSTM1), correlates with a higher incidence of heart failure and kidney disease. Our data reveal the Nrf2-dependent antioxidant gene program is stimulated in CF by exercise and is suppressed in heart disease in part through alterations in TGF-1 and ROS signaling. Importantly, we also find that Nrf2 stimulation through Keap1 depletion suppresses TGF-1 dependent fibroblast activation. Mechanistic studies using Drosophila revealed that moderate oxidant exposure maintains chromatin accessibility at NRF2-dependent antioxidant response elements, facilitating a dynamic antioxidant response to oxidative stress. In contrast, Nrf2-dependent antioxidant genes are suppressed by smoking or in aging, consistent with our findings in heart disease models, perhaps through “desensitization” to oxidant overabundance. Based on published research and our preliminary data, we hypothesize exercise leads to beneficial intracellular oxidant production that maintains Nrf2 responsiveness in cardiac fibroblasts, facilitating robust induction of the antioxidant gene program and suppression of fibrosis and cardiac remodeling in hypertensive heart disease. In this study we will utilize genetically modified mice and pharmacological approaches, in conjunction with cardiac physiology measurements and transcriptomics/genomic analyses to investigate a novel cardioprotective and anti-fibrotic mechanism of exercise. We will establish the anti-fibrotic benefits of exercise on cardiac fibrosis in a mouse model of hypertensive remodeling. We will define the impact of exercise on chromatin accessibility and gene expression using single nucleus ATAC/RNA-sequencing, focusing on antioxidant and fibrotic genes in CF. We will define how Nrf2 and Keap1 modulate the antioxidant and pro-fibrotic gene programs in CF to improve exercise tolerance and limit fibrosis and pathological cardiac remodeling. And we will investigate the anti-fibrotic mechanism of sulforaphane, a potent Keap1 inhibitor. Successful completion of the proposed experiments will help explain the cardioprotective benefits of exercise and establish a novel approach to prevent or reverse pathological cardiac fibrosis.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $665,724 )
2026	2026	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Cardiovascular Diseases Research	000	1	7/8/2026	NEW	$665,724
														Subtotal = $665,724

Grand Total All Awards = $665,724

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Establishing the role of exercise in the maintenance of a cardioprotective stress response

Award Number: R01HL178616

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/15/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2030

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer