# ARNT: A novel regulator of cardiac vascular endothelial barrier function in heart failure

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2020 · $411,515

## Abstract

Abstract
After a heart attack, restoring blood flow to the heart (i.e., reperfusion) is critically necessary to limit the amount
of myocardial tissue that is damaged by ischemic injury; however, reperfusion itself leads to its own type of
myocardial damage (ischemia-reperfusion [IR] injury) for which there is no treatment and that can lead to
chronic heart failure (HF). Thus, knowledge of the molecular mechanisms that are induced by cardiac
reperfusion is urgently needed to identify novel strategies for preventing IR injury. Cardiac edema, which is
mainly caused by an increase in cardiac vascular permeability, is one of the primary contributors to IR injury,
and the results from my preliminary studies indicate that vascular permeability is limited by the expression of
Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT), also known as hypoxia-inducible factor 1β, in
endothelial cells (ECs). I have recently generated a line of mice carrying an inducible, EC-specific ARNT
knockout mutation (ecARNT–/–), and the results from experiments with these mice indicate that the loss of
ecARNT expression during reperfusion leads to cardiac hemorrhage, and that when the ecARNT–/– mutation is
induced in adult animals, cardiac edema develops and gradually progresses to HF. Thus, ecARNT appears to
be a crucial regulator of endothelial barrier function, but the role of ecARNT in heart disease is not currently
being investigated. The experiments described in this proposal address this unmet need by studying the
mechanisms of ARNT-regulated endothelial barrier function after IR injury and their impact on the progression
of HF. Furthermore, our preliminary studies suggest that ARNT also regulates the expression of matrix
metalloproteinase 3 (MMP3), which cleaves proteins that form junctions between adjacent ECs; thus, we will
conduct in-vitro experiments with cultured ECs to determine whether MMP3 inhibition can reverse the impaired
endothelial barrier function associated with ecARNT deletion and if so, elucidate the mechanisms that support
this observation. We will also use the MMP3 inhibitors in ecARNT–/– mice and generate a line of
ecARNT/MMP3 double-knockout mice to determine whether MMP3 inhibition can restore vascular integrity and
limit the progression of IR-induced HF. Upon completion, we expect the results from our studies to have
identified new therapeutic targets and strategies for improving patient outcomes by reducing cardiac edema
during the early stages of recovery from a heart attack and preventing (or delaying) the progression of heart
disease.

## Key facts

- **NIH application ID:** 9838797
- **Project number:** 5R01HL140114-02
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Rongxue Wu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $411,515
- **Award type:** 5
- **Project period:** 2018-12-15 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838797

## Citation

> US National Institutes of Health, RePORTER application 9838797, ARNT: A novel regulator of cardiac vascular endothelial barrier function in heart failure (5R01HL140114-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9838797. Licensed CC0.

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