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September 17, 2026Clinical ScienceOpen Access

Fibroblast-enriched Kdm2a knockdown improves cardiac function and reduces hypertrophy and fibrosis in pressure-overloaded mice.

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Population

Mouse transverse aortic constriction (TAC) model and cultured primary cardiac fibroblasts

Comparison

Fibroblast-enriched Kdm2a knockdown and… vs Control mice/cells

Design

Preclinical

Key result

Fibroblast-enriched Kdm2a knockdown improved cardiac function, reduced myocardial hypertrophy, and markedly attenuated interstitial and perivascular fibrosis in a mouse model of pressure overload.

Authors

LWLianpin WuJCJiaqi ChenYWYizhe Wang

Discussion

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Overview

Positions Kdm2a as candidate antifibrotic target in HF; leaves open translation from murine models to patients.

Key Points

  • To elucidate the epigenetic role and molecular mechanisms of the histone demethylase Kdm2a in regulating cardiac fibroblast activation and myocardial fibrosis under pressure overload.
  • Induced cardiac pressure overload in mice via transverse aortic constriction (TAC) combined with fibroblast-enriched Kdm2a knockdown.
  • Modulated Kdm2a expression in cultured primary cardiac fibroblasts using CRISPR-mediated knockout and genetic overexpression following profibrotic stimulation.
  • Characterized gene expression and epigenetic alterations using RNA sequencing, network analyses, and CUT&RUN-qPCR to assess global and locus-specific H3K36me2 remodeling.
  • Fibroblast-enriched Kdm2a knockdown preserved left ventricular function, decreased myocardial hypertrophy, and significantly attenuated interstitial and perivascular fibrosis in TAC mice.
  • CRISPR-mediated Kdm2a knockout in primary fibroblasts repressed activation, collagen production, and extracellular matrix deposition, whereas Kdm2a overexpression promoted profibrotic activity.
  • Kdm2a modulated global H3K36me2 levels and directed locus-specific H3K36me2 chromatin remodeling at fibrotic and remodeling-associated gene loci, including Col1a1, Col4a1, and Cdkn2b/p15.

Structured PICO

P
Population
Mouse transverse aortic constriction (TAC) model and cultured primary cardiac fibroblasts
I
Intervention
Fibroblast-enriched Kdm2a knockdown (in vivo) and CRISPR-mediated Kdm2a knockout or overexpression (in vitro)
C
Comparator
Control mice/cells
O
Outcome
Cardiac function, myocardial hypertrophy, and fibrosis (interstitial and perivascular)surrogate

Kdm2a acts as an epigenetic driver of fibroblast-mediated cardiac remodeling and represents a potential therapeutic target for pressure overload-induced heart failure.

Cite This Study

Wu et al. (2026) studied Pressure overload-induced myocardial fibrosis. Kdm2a knockdown was evaluated on Cardiac remodeling and fibrosis. Fibroblast-enriched Kdm2a knockdown improved cardiac function, reduced myocardial hypertrophy, and markedly attenuated interstitial and perivascular fibrosis in a mouse model of pressure overload.

synapsesocial.com/papers/6aabb8045f706d05830e77e8https://doi.org/10.1042/cs20250850
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