Extracellular Vesicle-Derived circITGB1 Regulates Dendritic Cell Maturation and Cardiac Inflammation via miR-342-3p/NFAM1

Abstract

Acute myocardial infarction (AMI) is a complication of atherosclerosis-related cardiovascular illness that is caused by prolonged ischemia. Circular RNAs (circRNAs) are concentrated in extracellular vesicles (EVs) and have been linked to cardiovascular disease. However, additional research is needed into the expression and function of circRNAs in AMI. In this study, circITGB1 (has_circRNA_0018146), derived from exon 1 of the ITGB1 gene localized on chromosome 10, was shown to be considerably increased in plasma from patients with AMI compared to healthy controls, as demonstrated by the comparison of EV-circRNA expression patterns. Using a luciferase screening assay and a biotin-labeled circITGB1 probe to identify microRNA(s) complementary to circITGB1 sequences, we discovered that circITGB1 competitively binds to miR-342-3p and inhibits its expression, which in turn increase the expression of NFAT activating molecule 1 (NFAM1). Based on western blotting and immunological studies, circITGB1 controls dendritic cell maturation by targeting miR-342-3p and NFAM1. circITGB1 also exacerbated cardiac damage and regulated miR-342-3p and NFAM1 expression in a mouse AMI model. This implies that EV-circITGB1 is involved in dendritic cell maturation and cardiac damage via miR-342-3p/NFAM1, and that is linked to AMI-associated pathogenic processes.

Exosomes as a delivery tool of exercise-induced beneficial factors for the prevention and treatment of cardiovascular disease: a systematic review and meta-analysis

“…Second, long-term exercise-derived exosomal miR-342-5p not only targets the Caspase-9 and JNK2 pathways but also enhances survival signaling (p-Akt) by targeting the phosphatase gene Ppm1f to protect the heart from MI/R injury (Hou et al, 2019). From the same gene family, miR-342-3p has also been proven to participate in the regulatory processes related to acute myocardial infarction (AMI) by increasing the expression of NFAT activating molecule 1 (NFAM1) to combat myocardial injury (Zhu et al, 2022). Third, the expression of exercise-derived EV proteins ALIX and RAB35 activates ERK1/2 and HSP27 signals to protect against cardiac I/R injury (Bei et al, 2017).…”

Unraveling the Signaling Dynamics of Small Extracellular Vesicles in Cardiac Diseases

“…Another circRNA that also increases its expression in exosomes after MI is circITGB1. Within in vivo assays using a mouse model, these exosomes activate dendritic cells and exacerbate cardiac damage and inflammation through the miR-342-3p/NFAM1 pathway [86]. In vitro assays have also been reported in CMs subjected to hypoxia where high levels of circ_HIPK3 and circ_SLC8A1 are detected [87,88].…”

The Role of ncRNAs in Cardiac Infarction and Regeneration

“…Several circRNAs are upregulated in AMI patients, such as circITGB1 and circ_0023461, while studies have shown that circHelz and circ_0007059 are elevated in MI in mice [ 81 , 237 , 238 , 239 ]. Additionally, numerous other circRNAs are upregulated in experimental hypoxia models in vitro, such as circ_0023461, circHelz, circ_0007059, circ_0001747, circTRRAP, and circMAT2B [ 80 , 81 , 238 , 239 , 242 ].…”

“…circITGB1 controls dendritic cell maturation by targeting miR-342-3p and NFAM1. circITGB1 also exacerbated cardiac damage and regulated miR-342-3p and NFAM1 expression in a mouse AMI model [ 237 ]. Similarly, circ_0023461 expression is upregulated in AMI patients and hypoxia-induced AC16 cells, and it can upregulate PDE4D expression by acting as a molecular sponge for miR-370-3p in AC16 cells [ 238 ].…”