Abstract 4138819: KLF2-dependent transcriptional regulation safeguards the heart against pathological hypertrophy

BACKGROUND: 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. METHODS AND RESULTS: 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, comprehensive RNA sequencing analysis revealed that KLF2 exerts its protective effects by activating the Hippo signaling pathway and inhibiting the MAPK signaling pathway. In vivo, overexpression of KLF2 specifically in cardiomyocytes effectively prevents TAC-induced cardiac hypertrophy in mice. Furthermore, we found that simvastatin elevates KLF2 expression in cardiomyocytes, which in turn mitigates cardiomyocyte hypertrophy. CONCLUSIONS: 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.