# Spontaneous cardiac fibrosis in PAI-1-deficient mice and men: A rare mutation informs a common molecular pathophysiology

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2022 · $670,792

## Abstract

PROJECT SUMMARY
The fundamental objective of this research program is to advance our understanding of the pathogenesis
of cardiac fibrosis. Our recent identification of a novel familial fibrotic cardiomyopathy caused by a frame
shift mutation in SERPINE1 (the gene that codes for plasminogen activator inhibitor-1 [PAI-1]) in an Old
Order Amish kindred provides an exceptional opportunity to define the molecular pathophysiology of
cardiac fibrosis, a common complication of cardiac injury and manifestation of aging. We have previously
reported that mice and humans with complete genetic deficiency of PAI-1 undergo spontaneous age-
dependent cardiac selective fibrosis. We have also determined that PAI-1 regulates profibrotic signals by
cardiomyocytes (CMs), partially explaining why PAI-1-deficient mice undergo extensive fibrotic
cardiomyopathy during aging and cardiac injury. Although young PAI-1 deficient mice have normal
cardiac structure and function, they develop marked extracellular matrix (ECM) dysregulation, changes in
cardiac adhesion receptors, enhanced profibrotic signaling, and robust activation of myocardial
transcriptional networks that mediate the fibrotic response to stress. Based on these findings, we
hypothesize that PAI-1 serves as a pivotal regulator of cardiac fibrosis in mice and humans by 1)
controlling CM profibrotic cytokine generation, 2) regulating monocytic responses to cardiac injury, and 3)
modulating ECM-directed CM responses to stress. This application is composed of three specific Aims
designed to elucidate the cell-specific regulation of profibrotic signaling by PAI-1, via coordinated
investigation of novel tissue specific knockout mice that recapitulate the human disorder, a rare human
cohort with fibrotic cardiomyopathy, and a mechanistic determination of the effects of ECM components
on profibrotic signaling in the myocardium. The overarching goal for this proposal is to inform the
identification of novel therapeutic targets for prevention and treatment of cardiac fibrosis broadly through
the prism of genetic PAI-1 deficiency and the dysregulated cardiac ECM biology that follows. This project
utilizes a multi-disciplinary systems biology approach to understanding the function of the ECM networks
in the heart with aging and in response to stressors. We will use both established and new murine
models of age-dependent cardiac fibrosis to define the dynamic changes in cardiac ECM that precede
and precipitate fibrosis. We will extend the findings from our preclinical models with deep phenotyping of
a unique cohort of humans with a familial fibrotic cardiomyopathy due to complete PAI-1 deficiency. We
will build upon our observations from age-dependent cardiac fibrosis models by critically examining how
individual ECM substrates regulate the epigenetic and synthetic programs of mouse and human CMs
during injury and define how PAI-1 deficiency augments myocyte-fibroblast-macrophage communication
to enhance cardiac fibrosis.

## Key facts

- **NIH application ID:** 10402774
- **Project number:** 5R01HL142761-04
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Douglas E Vaughan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $670,792
- **Award type:** 5
- **Project period:** 2019-04-15 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10402774

## Citation

> US National Institutes of Health, RePORTER application 10402774, Spontaneous cardiac fibrosis in PAI-1-deficient mice and men: A rare mutation informs a common molecular pathophysiology (5R01HL142761-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10402774. Licensed CC0.

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