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Cardiac reprogramming and Gata4 overexpression reduce fibrosis and improve diastolic dysfunction in heart failure with preserved ejection fraction [Visium]

ABSTRACT: Fibrosis is important pathogenesis in heart failure with preserved ejection fraction (HFpEF). We previously reported that the overexpression of cardiac transcription factors, Mef2c/Gata4/Tbx5/Hand2 (MGTH) could directly reprogram cardiac fibroblasts (CFs) into induced CMs (iCMs) and reduce fibrosis. Here we show that in vivo cardiac reprogramming generated iCMs from resident CFs, improved cardiac function, and reversed fibrosis in HFpEF model using a novel transgenic mouse system. Visium revealed spatial information on changes in gene expression in HFpEF.

ORGANISM(S): Mus musculus

PROVIDER: GSE218759 | GEO | 2024/12/14

REPOSITORIES: GEO

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Project description:Aims: Heart failure with preserved ejection fraction (HFpEF) is a multifactorial disease that constitutes several distinct phenotypes, including a common cardiometabolic phenotype with obesity and type 2 diabetes mellitus. Treatment options for HFpEF are limited, and development of novel therapeutics is hindered by the paucity of suitable preclinical HFpEF models that recapitulate the complexity of human HFpEF. Metabolic drugs, like Glucagon Like Peptide Receptor Agonist (GLP-1RA) and Sodium Glucose Transporter 2 inhibitors (SGLT2i), have emerged as promising drugs to restore metabolic perturbations and may have value in the treatment of the cardiometabolic HFpEF phenotype. We aimed to develop a multifactorial HFpEF mouse model that closely resembles the cardiometabolic HFpEF phenotype, and evaluated the GLP-1 RA liraglutide and a SGLT2i dapagliflozin. Methods&Results: Aged (18-22 months old) female C57BL/6J mice were fed a standardized chow (CTRL) or high fat diet (HFD) for 12 weeks. After 8 weeks HFD, Angiotensin-II (ANGII), was administered for 4 weeks via osmotic mini-pumps. HFD+ANGII resulted in a cardiometabolic HFpEF phenotype, including obesity, impaired glucose handling and metabolic dysregulation with inflammation. The multiple-hit resulted in typical clinical HFpEF features, including cardiac hypertrophy and fibrosis with preserved fractional shortening but with impaired myocardial deformation, atrial enlargement lung congestion, and elevated blood pressures. Treatment with liraglutide attenuated the cardiometabolic dysregulation and improved cardiac function, with reduced cardiac hypertrophy, less myocardial fibrosis, and attenuation of atrial weight, natriuretic peptide levels, and lung congestion. Dapagliflozin treatment improved glucose handling, but had mild effects on the HFpEF phenotype. Conclusions: We developed a mouse model that recapitulates the human HFpEF disease, providing a novel opportunity to study disease pathogenesis and development of enhanced therapeutic approaches. We furthermore show that attenuation of cardiometabolic dysregulation may represent a novel therapeutic target for treatment of HFpEF.

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Cardiac reprogramming and Gata4 overexpression reduce fibrosis and improve diastolic dysfunction in heart failure with preserved ejection fraction [Visium]

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