Let-7e-5p promotes cardiac hypertrophy by targeting LBH and regulating the IGF–PI3K–AKT signaling pathway

BACKGROUND: Cardiac hypertrophy refers to the compensatory response of the heart to various physiological or pathological stimuli in order to maintain its function. Let-7e-5p has been reported to be upregulated in patients with cardiac hypertrophy. OBJECTIVES: This study aimed to investigate the role of let-7e-5p in the progression of cardiac hypertrophy using animal and cell models. MATERIAL AND METHODS: Peripheral blood was collected from patients with cardiac hypertrophy and healthy controls to detect let-7e-5p expression via reverse transcription quantitative polymerase chain reaction (RT-qPCR). An aortic banding (AB)-induced cardiac hypertrophy rat model was established to explore let-7e-5p expression in vivo. Antagomir let-7e-5p was used to investigate the effects of let-7e-5p silencing on cardiac hypertrophy progression in an AB-induced rat model. Angiotensin II (Ang II) was used to induce hypertrophy in H9c2 rat cardiomyocytes in vitro. The downstream regulatory mechanism of let-7e-5p was investigated in H9c2 cells. RESULTS: We first examined and verified that let-7e-5p was upregulated in blood samples from patients with hypertrophic cardiomyopathy (HCM) compared to healthy controls and showed good diagnostic performance according to receiver operating characteristic (ROC) analysis. In vivo, let-7e-5p was overexpressed in the heart tissues of AB-induced cardiac hypertrophy rats. Let-7e-5p deficiency alleviated AB surgery-induced cardiac hypertrophy in rat models. In vitro, let-7e-5p expression was higher in Ang II-induced H9c2 rat cardiomyocytes. Let-7e-5p inhibition reversed the Ang II-induced increase in cardiomyocyte size and the upregulation of ANP, BNP, and β-MHC expression, whereas let-7e-5p overexpression showed the opposite effects. Mechanistically, limb-bud and heart (LBH) was identified as a target of let-7e-5p, and LBH overexpression reversed the promotive effects of let-7e-5p on hypertrophy in Ang II-treated H9c2 cells. IGF-PI3K-AKT signaling was activated in Ang II-treated H9c2 cells, and let-7e-5p silencing suppressed its activation by targeting LBH. The IGF1R inhibitor PQ401 reversed the enhancement of H9c2 hypertrophy induced by let-7e-5p upregulation or LBH silencing. CONCLUSIONS: Let-7e-5p promotes cardiac hypertrophy by targeting LBH and regulating the IGF-PI3K-AKT signaling pathway, which may provide novel insights into targeted therapy.