Cardiac Reprogramming and Gata4 Overexpression Reduce Fibrosis and Improve Diastolic Dysfunction in Heart Failure...

Area of Science:

• Cardiology
• Regenerative Medicine
• Fibrosis Research

Background:

• Heart failure with preserved ejection fraction (HFpEF) is a significant health concern characterized by cardiac fibrosis and diastolic dysfunction.
• Mechanisms driving fibrosis in HFpEF are not fully understood, and effective targeted therapies are lacking.
• Cardiac reprogramming, involving overexpression of Mef2c/Gata4/Tbx5/Hand2 (MGTH), has shown potential for myocardial infarction but its efficacy in HFpEF is unknown.

Purpose of the Study:

• To investigate the efficacy of cardiac reprogramming in a mouse model of HFpEF.
• To elucidate the mechanisms underlying cardiac fibrosis in HFpEF.
• To evaluate the therapeutic potential of individual reprogramming factors, particularly Gata4, in HFpEF.

Main Methods:

• Established HFpEF model mice using a high-fat diet and nitric oxide synthase inhibition.
• Utilized transgenic mice for tamoxifen-inducible MGTH overexpression in cardiac fibroblasts (CFs) for reprogramming and lineage tracing.
• Employed bulk RNA-sequencing, single-cell RNA-sequencing, and spatial transcriptomics to analyze fibrotic mechanisms and reprogramming effects.
• Investigated the impact of single reprogramming factors and their effects on human CFs.

Main Results:

• MGTH overexpression improved diastolic dysfunction, cardiac hypertrophy, fibrosis, inflammation, and capillary loss in HFpEF mice.
• Cardiac reprogramming converted approximately 1% of CFs into induced cardiomyocytes, upregulated heart contraction genes, and suppressed fetal gene programs and profibrotic signatures.
• Single-cell and spatial transcriptomics revealed MGTH reversed profibrotic changes in distinct CF clusters responsible for interstitial and perivascular fibrosis.
• Gata4 overexpression alone reduced fibrosis and improved diastolic dysfunction by suppressing CF activation without inducing new cardiomyocytes, and also suppressed profibrotic signatures in human CFs.

Conclusions:

• Overexpression of Gata4 in cardiac fibroblasts (CFs) presents a promising therapeutic strategy for HFpEF.
• Gata4-mediated reprogramming effectively suppresses cardiac fibrosis and ameliorates diastolic dysfunction in HFpEF.
• Targeting CF activation through Gata4 offers a potential new avenue for treating HFpEF.