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KLF2-dependent transcriptional regulation safeguards the heart against pathological hypertrophy

ABSTRACT: Our previous single-cell RNA sequencing study in the adult human heart revealed that cardiomyocytes from both the atrium and ventricle display high activities of Krüppel-like factor 2 (KLF2) regulons. However, the role of the transcription factor KLF2 in cardiomyocyte biology remains largely unexplored. We employed transverse aortic constriction surgery in male C57BL/6J mice to develop an in vivo model of cardiac hypertrophy, and generated different in vitro cardiac hypertrophy models in neonatal rat ventricular myocytes and human embryonic stem cell-derived cardiomyocytes. Our results demonstrated a significant reduction in KLF2 expression during the progression of cardiac hypertrophy. In vitro, KLF2 deficiency exacerbates cardiac hypertrophy and enhances hypertrophic reprogramming, while KLF2 overexpression attenuates cardiac hypertrophy and reverses hypertrophic transcriptome reprogramming. Mechanistically, combined RNA-seq and cleavage under targets & tagmentation (CUT&Tag) analysis revealed that KLF2 exerts its protective effects by directly regulating a set of genes associated with cardiac hypertrophy. In vivo, KLF2 overexpression specifically in cardiomyocytes effectively prevents TAC-induced cardiac hypertrophy in mice. Additionally, we found that simvastatin elevates KLF2 expression in cardiomyocytes, which subsequently alleviates cardiomyocyte hypertrophy. This study provides the first evidence that transcription factor KLF2 serves as a negative regulator of cardiac hypertrophy. Our findings highlight the therapeutic potential of enhancing KLF2 expression, particularly through simvastatin administration, as a promising strategy in the treatment of cardiac hypertrophy.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE283973 | GEO | 2025/01/01

REPOSITORIES: GEO

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Project description:Cardiomyocytes exhibit differential growth patterns throughout development. In fetal life the increase in cardiac mass is associated with hyperplastic growth and cardiomyocyte proliferation. The majority of fetal cardiomyocytes are also mononucleated. During the early neonatal period in mice there is a switch from hyperplastic to hypertrophic growth of cardiomyocytes. This period is characterized by bi-nucleation and polyploidization of cardiomyocyte nuclei and a decreased capacity for cardiomyocytes to proliferate and complete cytokinesis. Increases in myocardial mass occur predominantly via hypertrophic growth. Adult mammalian cardiomyocytes are generally accepted to have little or no proliferative capacity and to be terminally withdrawn from the cell cycle. The vast majority of adult murine cardiomyocytes are bi-nucleated. The present study sought to accurately establish the growth pattern of cardiomyocytes throughout development in mice and identify genes associated with the switch from hyperplastic to hypertrophic growth. These cell cycle associated genes are crucial to the understanding of the mechanisms of bi-nucleation, polyploidization and hypertrophy in the neonatal period. Cardiomyocytes were FACS sorted from the hearts of ED11-12 embryos, neonatal day 3-4 and adult (10 week) eGFP ?-MHC mice whereby GFP expression is driven constitutively by the ?-MHC promoter. Gene analyses identified genes whose expression was predicted to be particular to day 3 -4 neonatal cardiomyocytes, compared to embryonic or adult cells. Cell cycle associated genes are crucial to the understanding of the mechanisms of bi-nucleation and hypertrophy in the neonatal period, and offer attractive candidates for manipulation. Total RNA obtained from isolated cardiomyocytes from ED11-12; Neonatal day 3-4 and adult timepoints compared with each other. Several hearts per sample, RNA was pooled within samples. FACS samples were prepared in the following manner: embryonic, neonatal and adult hearts were dissected and dissociated to single cell solution with Liberase Blendzyme 3 (0.1 mg/ml) (Roche Diagnostics), washed and spun down and resuspended in cardiomyocyte isolation buffer (130 mM NaCl; 5 mM KCl; 1.2 mM KH2PO4; 6 mM HEPES; 5 mM NaHCO3; 1 mM MgCl2; 5 mM Glucose).

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KLF2-dependent transcriptional regulation safeguards the heart against pathological hypertrophy

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