# Targeting Resident Cardiac Fibroblast Subpopulations for Protection Against Fibrosis

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2022 · $599,533

## Abstract

PROJECT SUMMARY/ABSTRACT
Hypertension stimulates cardiac fibroblast (CF) expansion, activation, and excess extracellular matrix (ECM)
production. Although there are no approved treatments for cardiac fibrosis, angiotensin converting enzyme
inhibition (ACEi) limits CF activation and ECM accumulation. Recent findings from the laboratory of the PI
demonstrate that resident CFs, once considered functionally homogeneous, consist of physiologically distinct
populations that differentiate to diverse phenotypes in response to pressure overload. The premise for this
application is based on these findings in which hypertensive rats were transiently treated with an ACEi prior to
single cell RNA sequencing on resident CFs. Pre-treatment with ACEi shifts CF subpopulations to generate
homeostatic CFs with a reduced capacity for fibrosis. This effect persists after treatment is stopped, indicating
memory is retained. The proposed studies will reveal the mechanisms by which CF subpopulations shift to
determine how to reprogram CFs to display a homeostatic, less fibrogenic phenotype. Following ACEi,
homeostatic CFs comprise the largest subpopulation of resident CFs and are the least fibrogenic. Trajectory
analysis revealed a gateway CF subpopulation that is the immediate precursor to activated CFs, and this
gateway cluster was the most depleted by ACEi. Gateway CFs were defined by high expression of Spp1,
encoding for the protein osteopontin, which induces several pro-fibrotic genes and represents a critical target
candidate to maintain the activated CF pool. ACEi altered expression of epigenetic genes, indicating changes
in chromatin structure may drive the persistent shift from gateway to homeostatic CF subpopulations. These
compelling preliminary results led to the central hypothesis: transient reduction in angiotensin II signaling alters
CF memory to protect against left ventricle (LV) fibrosis by fibroblast subpopulation-specific reprogramming of
chromatin structure to shift an osteopontin-producing gateway subpopulation toward a homeostatic
subpopulation with low fibrogenic capacity. To test the hypothesis, the following specific aims are proposed:
Aim 1) elucidate the degree to which reduction in angiotensin II signaling mediates the persistent shift in
resident CF physiology that protects from future fibrosis; Aim 2) determine the impact of chromatin structural
modification on shifting the gateway cluster toward the homeostatic cluster; and Aim 3) ascertain the degree to
which reduction in osteopontin mediates the shift to a less fibrogenic phenotype. In this application, the
research team uses a multidisciplinary approach employing in vivo and in vitro methodologies to test the
hypothesis. Successful completion of these experiments will determine whether reduction in angiotensin II
signaling mediates the expansion of a subset of homeostatic CFs that renders the LV resistant to fibrosis. It is
expected that the key drivers regulating the shift from a gate...

## Key facts

- **NIH application ID:** 10363496
- **Project number:** 1R01HL153112-01A1
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Taben M. Hale
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $599,533
- **Award type:** 1
- **Project period:** 2022-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10363496

## Citation

> US National Institutes of Health, RePORTER application 10363496, Targeting Resident Cardiac Fibroblast Subpopulations for Protection Against Fibrosis (1R01HL153112-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10363496. Licensed CC0.

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