What question did this study set out to answer?

To evaluate whether cardiac reprogramming via transcription factor overexpression can resolve cardiac fibrosis and diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF).

December 14, 2024Circulation

Cardiac Reprogramming and Gata4 Overexpression Reduce Fibrosis and Improve Diastolic Dysfunction in Heart Failure With Preserved Ejection Fraction

Q: What is the clinical evidence from this study?

Study design: Other. Population: Heart failure with preserved ejection fraction (HFpEF). Intervention: Cardiac reprogramming with MGTH or Gata4 overexpression. Primary outcome: Diastolic dysfunction, cardiac hypertrophy, fibrosis, inflammation, and capillary loss.

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Key result

Cardiac reprogramming with MGTH or Gata4 overexpression in cardiac fibroblasts reduced fibrosis and improved diastolic dysfunction in a mouse model of HFpEF.

Why the study?

Mechanisms of cardiac fibrosis in HFpEF remain poorly elucidated with targeted therapies lacking, and the efficacy of cardiac reprogramming has not been established in HFpEF.

Does cardiac reprogramming via MGTH or Gata4 overexpression reduce fibrosis and improve diastolic dysfunction in preclinical models of HFpEF?

Population

Transgenic HFpEF model mice and human CFs

Comparison

Cardiac reprogramming via MGTH or single factor overexpression in CFs

Design

Preclinical animal and in vitro mechanistic study

Authors

YYYu YamadaUniversity of Tsukuba TSTaketaro SadahiroKeio University KNKoji NakanoHiroshima University

Discussion

Member takes

Overview

Hypothesis-generating for cardiac reprogramming in HFpEF; leaves open translation to humans.

Key Points

To evaluate whether cardiac reprogramming via transcription factor overexpression can resolve cardiac fibrosis and diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF).
Induced HFpEF in transgenic lineage-tracing mice using a high-fat diet and nitric oxide synthase inhibition, followed by tamoxifen-induced fibroblast-specific overexpression of Mef2c/Gata4/Tbx5/Hand2 (MGTH) or individual factors.
Performed bulk RNA-sequencing, single-cell RNA-sequencing, and spatial transcriptomics to profile fibroblast heterogeneity and evaluated functional responses in mouse and human cardiac fibroblasts.
MGTH overexpression converted ~1% of resident cardiac fibroblasts into induced cardiomyocytes, downregulated fetal/inflammatory genes (Nppa, Nppb), and mitigated hypertrophy, capillary loss, and diastolic dysfunction.
Single-cell and spatial profiling identified distinct fibroblast subsets driving diffuse interstitial versus focal perivascular fibrosis, both of which were reversed by reprogramming.
Gata4 overexpression alone was sufficient to deactivate cardiac fibroblasts, reduce fibrosis, and improve diastolic dysfunction in mice and suppress profibrotic signatures in human cardiac fibroblasts without generating new cardiomyocytes.

Structured PICO

Does cardiac reprogramming via MGTH or Gata4 overexpression reduce fibrosis and improve diastolic dysfunction in preclinical models of HFpEF?

Population

Tcf21 iCre /Tomato/MGTH2A transgenic mice and other tamoxifen-inducible transgenic mice with HFpEF induced by high-fat diet and nitric oxide synthase inhibition, and human cardiac fibroblasts.

Intervention

Cardiac reprogramming via Mef2c/Gata4/Tbx5/Hand2 (MGTH) overexpression or single factor (Gata4) overexpression in resident cardiac fibroblasts.

Outcome

Diastolic dysfunction, cardiac hypertrophy, fibrosis, inflammation, and capillary loss.surrogate

Overexpressing Gata4 in cardiac fibroblasts reduces fibrosis and improves diastolic dysfunction in preclinical models of HFpEF, suggesting a potential novel therapeutic target.

Cite This Study

Yamada et al. (2024) studied Heart failure with preserved ejection fraction (HFpEF). Cardiac reprogramming with MGTH or Gata4 overexpression was evaluated on Diastolic dysfunction, cardiac hypertrophy, fibrosis, inflammation, and capillary loss. Cardiac reprogramming with MGTH or Gata4 overexpression in cardiac fibroblasts reduced fibrosis and improved diastolic dysfunction in a mouse model of HFpEF.

synapsesocial.com/papers/6a7d89c17c193befc43395df https://doi.org/10.1161/circulationaha.123.067504

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December 14, 2024Circulation

Cardiac Reprogramming and Gata4 Overexpression Reduce Fibrosis and Improve Diastolic Dysfunction in Heart Failure With Preserved Ejection Fraction

View Full Paper

Ask AI

Bookmark

Key result

Cardiac reprogramming with MGTH or Gata4 overexpression in cardiac fibroblasts reduced fibrosis and improved diastolic dysfunction in a mouse model of HFpEF.

Why the study?

Mechanisms of cardiac fibrosis in HFpEF remain poorly elucidated with targeted therapies lacking, and the efficacy of cardiac reprogramming has not been established in HFpEF.

Does cardiac reprogramming via MGTH or Gata4 overexpression reduce fibrosis and improve diastolic dysfunction in preclinical models of HFpEF?

Population

Transgenic HFpEF model mice and human CFs

Comparison

Cardiac reprogramming via MGTH or single factor overexpression in CFs

Design

Preclinical animal and in vitro mechanistic study

Authors

YYYu YamadaUniversity of Tsukuba TSTaketaro SadahiroKeio University KNKoji NakanoHiroshima University

Discussion

Member takes

Overview

Hypothesis-generating for cardiac reprogramming in HFpEF; leaves open translation to humans.

Key Points

To evaluate whether cardiac reprogramming via transcription factor overexpression can resolve cardiac fibrosis and diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF).
Induced HFpEF in transgenic lineage-tracing mice using a high-fat diet and nitric oxide synthase inhibition, followed by tamoxifen-induced fibroblast-specific overexpression of Mef2c/Gata4/Tbx5/Hand2 (MGTH) or individual factors.
Performed bulk RNA-sequencing, single-cell RNA-sequencing, and spatial transcriptomics to profile fibroblast heterogeneity and evaluated functional responses in mouse and human cardiac fibroblasts.
MGTH overexpression converted ~1% of resident cardiac fibroblasts into induced cardiomyocytes, downregulated fetal/inflammatory genes (Nppa, Nppb), and mitigated hypertrophy, capillary loss, and diastolic dysfunction.
Single-cell and spatial profiling identified distinct fibroblast subsets driving diffuse interstitial versus focal perivascular fibrosis, both of which were reversed by reprogramming.
Gata4 overexpression alone was sufficient to deactivate cardiac fibroblasts, reduce fibrosis, and improve diastolic dysfunction in mice and suppress profibrotic signatures in human cardiac fibroblasts without generating new cardiomyocytes.

Structured PICO

Does cardiac reprogramming via MGTH or Gata4 overexpression reduce fibrosis and improve diastolic dysfunction in preclinical models of HFpEF?

Population

Tcf21 iCre /Tomato/MGTH2A transgenic mice and other tamoxifen-inducible transgenic mice with HFpEF induced by high-fat diet and nitric oxide synthase inhibition, and human cardiac fibroblasts.

Intervention

Cardiac reprogramming via Mef2c/Gata4/Tbx5/Hand2 (MGTH) overexpression or single factor (Gata4) overexpression in resident cardiac fibroblasts.

Outcome

Diastolic dysfunction, cardiac hypertrophy, fibrosis, inflammation, and capillary loss.surrogate

Overexpressing Gata4 in cardiac fibroblasts reduces fibrosis and improves diastolic dysfunction in preclinical models of HFpEF, suggesting a potential novel therapeutic target.

Cite This Study

synapsesocial.com/papers/6a7d89c17c193befc43395df https://doi.org/10.1161/circulationaha.123.067504

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