circ_CHFR regulates ox-LDL-mediated cell proliferation, apoptosis, and EndoMT by miR-15a-5p/EGFR axis in human brain microvessel endothelial cells

Abstract

Oxidized low-density lipoprotein (ox-LDL) is a significant risk factor for various brain vascular diseases. Circular RNA (circRNA) is involved in the pathogenesis of brain vascular diseases. This study revealed the roles of circ_CHFR in ox-LDL-mediated cell proliferation, apoptosis, and endothelial-to-mesenchymal transition (EndoMT). Our results showed that circ_CHFR and EGFR expressions were dramatically upregulated, while miR-15a-5p expression was downregulated in ox-LDL-induced human brain microvessel endothelial cells (HBMECs) relative to control groups. circ_CHFR knockdown hindered the effects of ox-LDL exposure on cell proliferation, cell cycle, apoptosis, and EndoMT in HBMECs, whereas these impacts were abolished by miR-15a-5p inhibitor. In addition, circ_CHFR functioned as a sponge of miR-15a-5p and miR-15a-5p bound to EGFR. Thus, we concluded that circ_CHFR silencing hindered ox-LDL-mediated cell proliferation, apoptosis, and EndoMT by downregulating EGFR expression through sponging miR-15a-5p in HBMECs. Our findings provide a new mechanism for studying circRNA-directed therapy in ox-LDL-induced human brain vascular diseases.

The uPA/uPAR System Orchestrates the Inflammatory Response, Vascular Homeostasis, and Immune System in Fibrosis Progression

“…EGFR activation promotes an increase in myofibroblasts [ 112 ]. EGF neutralization inhibits myofibroblast proliferation [ 113 ], and the inhibition of EGFR signaling blocks EMT and EndoMT [ 114 , 115 ]. The inhibition of PDGFR promotes a reduction in myofibroblasts [ 116 ] and interferes with EMT [ 117 ].…”

Circular RNA as Therapeutic Targets in Atherosclerosis: Are We Running in Circles?

“…These studies suggest contradictory effects via similar mechanisms of miR-370 inhibition (Figure 3). [43,85,128]. However, circCHFR has also been demonstrated to (2) reduce the expression of miR-370 [21], the inhibition of which has also been shown to have opposing effects compared to circCHFR via sponging by (3) circ-BANP and (4) circ_0124644 [45,121].…”

“…While most studies also observed that circCHFR was up-regulated in the serum of patients with atherosclerosis, this up-regulation may lead to the promotion of some genes that foster protective effects against atherosclerosis. [43,85,128]. However, circCHFR has also been demonstrated to (2) reduce the expression of miR-370 [21], the inhibition of which has also been shown to have opposing effects compared to circCHFR via sponging by (3) circ-BANP and (4) circ_0124644 [45,121].…”

Role of Circular RNAs in Atherosclerosis through Regulation of Inflammation, Cell Proliferation, Migration, and Apoptosis: Focus on Atherosclerotic Cerebrovascular Disease

“…Circ_CHFR (checkpoint with forkhead-associated and ring-finger domains) is a circRNA marked by the CHFR gene, which is involved in VEMC and EC proliferation and migration [ 140 , 141 ]. Circ_CHFR was significantly increased in serum from patients with AS and several types of in vitro cells, such as VSMCs, ECs, and human brain microvessel endothelial cells (HBMECs) [ 141 , 142 , 143 ]. There are several pathways and mechanisms that contribute to AS, including the miR-214-3p/Wnt3/β-catenin and miR-370/FOXO1/Cyclin D1 axes [ 140 , 142 ].…”

“…There are several pathways and mechanisms that contribute to AS, including the miR-214-3p/Wnt3/β-catenin and miR-370/FOXO1/Cyclin D1 axes [ 140 , 142 ]. Cell cycle arrest occurred at the G0/G1 phase upon ox-LDL treatment in HBMECs, but a circ_CHFR inhibitor attenuated this effect mediated by miR15a-5p [ 141 ]. An analysis of circ_CHFR and some miRNA sequences suggested that there were several complementary binding sites within circ_CHFR and miRNAs [ 140 , 143 , 144 ], indicating that circ_CHFR can sponge miRNA [ 142 ].…”