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

BackgroundCardiac 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.MethodsTransverse 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.ResultsTFRC 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).ConclusionThis 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.

A novel circPIK3C2A/miR‐31‐5p/TFRC axis drives ferroptosis and accelerates myocardial injury

“… 21 , 22 In addition, TFRC was reported to induce macrophage activation and infiltration through STAT3‐Ccl2 signaling pathway, promoting the development of heart failure. 23 In our study, iron levels were significantly increased in I/R group (6.926 ± 0.3414 vs. 12.52 ± 0.4135; Figures 6C and 7D ), the combination of HID and I/R resulted in significant myocardial damage and cardiac dysfunction. Beyond the high expression of TFRC, it remains to be further investigated whether there are other mechanisms that mediate iron overload.…”

Identification CCL2,CXCR2,S100A9 of the immune-related gene markers and immune infiltration characteristics of inflammatory bowel disease and heart failure via bioinformatics analysis and machine learning

“…CCL2 can promote cardiac decompensation ( 40 ), and upregulation in stressed and injured cardiomyocytes ( 41 ). TFRC in cardiomyocytes recruits and activates macrophages by secreting CCL2 to induce myocardial hypertrophy and promote HF development ( 42 ). Daniela Impellizzeri et al found that pro-inflammatory mediator CCL2 was significantly upregulated in inflammation of the colon and is associated with increased disease activity ( 43 ).…”