TFRC in cardiomyocytes promotes macrophage infiltration and activation during the process of heart failure through regulating Ccl2 expression mediated by hypoxia inducible factor-1α.

ABSTRACT

BACKGROUND: Cardiac hypertrophy is an initiating link to Heart failure (HF) which still seriously endangers human health. Transferrin receptor (TFRC), which promotes iron uptake through the transferrin cycle, is essential for cardiac function. However, whether TFRC is involved in the process of pathological cardiac hypertrophy is not clear. METHODS: Transverse aortic constriction (TAC) mouse model and mice primary cardiomyocytes treated with isoproterenol (ISO) or phenylephrine (PHE) were used to mimic cardiac hypertrophy in vivo and in vitro. Single cell RNA sequence data from heart tissues of TAC-model mice was obtained from the Gene Expression Omnibus (GEO) database, and was analyzed with R package Seurat. TFRC expression and macrophage infiltration in the heart tissue were tested by immunofluorescent staining. Macrophage polarization was detected by Flow Cytometry. TFRC expressions were detected by qRT-PCR, Western blot, and ELISA. RESULTS: TFRC expression is increased in the pathological cardiac hypertrophy of mice model and positively associated with macrophage infiltration. Furthermore, TFRC in cardiomyocytes recruits and activates macrophages by secreting C-C motif ligand 2 (Ccl2) in the mice heart tissue with TAC surgery or in the primary cardiomyocytes stimulated with ISO or PHE to induce myocardial hypertrophy in vitro. Moreover, we find that TFRC promotes Ccl2 expression in cardiomyocytes via regulating signal transducer and activator of transcription 3 (STAT3). In addition, we find that increased TFRC expression in the HF tissue is regulated by hypoxia-inducible factor-1α (HIF-1α). CONCLUSION: This in-depth study shows that TFRC in cardiomyocytes promotes HF development through inducing macrophage infiltration and activation via the STAT3-Ccl2 signaling, and TFRC expression in cardiomyocytes is regulated by HIF-1α during HF. This study first uncovers the role of TFRC in cardiomyocytes on macrophage infiltration and activation during HF.