Project Details
Description
PROJECT SUMMARY
Heart failure is associated with activation of cardiac fibroblasts (Fib), which promotes cardiac fibrosis and
pathological cardiac remodeling. Employing single-cell RNA-sequencing (scRNA-seq) in adult mouse hearts, we
discovered that Enhancer of Zeste homolog 2 (EZH2), the major enzyme known to catalyze the transcriptional
repression mark H3K27me3, is highly expressed in a specific POSTN+ Fib subpopulation (myofibroblasts, MFib).
Of note, little is known about the functional role of EZH2 in regulating cardiac MFib, which is a critical knowledge
gap given their epigenetic variability and pathological role. We demonstrate that although these MFib express
GATA4, an early cardiac transcription factor, they fail to express the cardiovascular progenitor (CPC) gene
programs, such as NKX2.5. Importantly, deletion of EZH2 inhibited MFib proliferation and switched on
cardiovascular progenitor cell (CPC) gene programs. Moreover, deletion of EZH2 increased the pro-angiogenic
paracrine effects of MFib and improved cardiac function post myocardial infarction (MI) These beneficial effects
on cardiac function were lost in mice administered a novel rAAV-FLEX-DTA vector, which ablates MFib lacking
EZH2, confirming the important functional role of this cell population. These findings suggest that EZH2 is a
restraint on the transition of MFib to beneficial phenotypes and that inhibition of EZH2 provides a unique
therapeutic approach to diminishing MFib proliferation while activating repair mechanisms. The overall goal of
this project is to test the central hypothesis that EZH2 inhibition in myofibroblasts can transform the cell fate
from pro-fibrotic myofibroblasts into pro-angiogenic CPC, thus attenuating fibrosis, improving cardiac
angiogenesis, and boosting cardiac repair in the ischemic myocardium. This proposed project is innovative
because it will generate unique mechanistic insights from novel approaches to cardiac regeneration by
transforming cardiac myofibroblasts from a proliferative and pro-fibrotic phenotype to a pro-angiogenic and pro-
regenerative phenotype. Our focus on EZH2-mediated chromatin remodeling in epigenetic repression of
GATA4-mediated CPC program is translationally significant, as EZH2 inhibitors are available clinically and have
recently been approved for the treatment of follicular lymphoma. Our preliminary findings highlight the potential
for this pathway to be the focus of novel strategies for mitigating cardiac fibrosis and promoting cardiac
angiogenesis after ischemic injury.
Status | Active |
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Effective start/end date | 7/1/23 → 6/30/24 |
Funding
- National Heart, Lung, and Blood Institute: $509,007.00
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