Inhibition of IL-8-mediated endothelial adhesion, VSMCs proliferation and migration by siRNA-TMEM98 suggests TMEM98's emerging role in atherosclerosis

Lv, Guixia; Zhu, Hongmei; Cai, Li; Wang, Jingyu; Zhao, Dandan; Li, Shuyao; Ma, Le; Sun, Guohua; Li, Fang; Zhao, Ying; Gao, Ying

doi:10.18632/oncotarget.21408

Cited by 18 publications

(13 citation statements)

References 34 publications

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“…Compelling evidence has delineated the involvement of IL-8 and its receptors CXCR1/2 in the pathogenesis of several diseases including rheumatoid arthritis, inflammatory bowel disease, chronic obstructive pulmonary diseases, asthma, and cancers [10]. Recently, IL-8 has been identified as a critical regulator in the function of endothelial cells (ECs) and vascular smooth muscles cells (VSMCs); therefore, it is likely to participate in the development of AS [11]. A previous study reported that lymphoma-derived IL-8 induced NETs formation via interacting with CXCR2; NETs formation further promoted tumor cell proliferation and migration [12].…”

Section: Introductionmentioning

confidence: 99%

Neutrophil extracellular traps induced by IL-8 aggravate atherosclerosis via activation NF-κB signaling in macrophages

An¹,

et al. 2019

Cell Cycle

175

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Here, we sought to explore the underlying role of interleukin (IL)-8 in neutrophil extracellular traps (NETs) formation during atherosclerosis (AS). The concentration of pro-inflammatory cytokines IL-8, IL-6 and IL-1β was determined by enzyme-linked immunosorbent assay (ELISA). NETs formation was evaluated by immunofluorescence and myeloperoxidase (MPO)-DNA complex ELISA. The mRNA levels of IL-8 and Toll-like receptor 9 (TLR9) were measured by quantitative real-time PCR (qRT-PCR). The phosphorylation levels of NF-κB p65 were detected by western blotting. The hematoxylin and eosin (H&E) staining of atherosclerotic lesion areas was performed in ApoE-deficiency mice. Results showed that patients with AS showed higher serum levels of IL-8, a pro-inflammatory cytokine and NETs. IL-8 interacted with its receptor CXC chemokine receptor 2 (CXCR2) on neutrophils, leading to the formation of NETs via Src and extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinases (MAPK) signaling to aggravate AS progression in vivo. PMA-induced NETosis directly upregulated the TLR9/NF-κB pathway in macrophages and subsequently initiated the release of IL-8. Our data reveal a neutrophil-macrophage interaction in AS progression, and indicate that NETs represent as a novel therapeutic target in treatment of AS and other cardiovascular diseases (CVD).

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Section: Introductionmentioning

confidence: 99%

Neutrophil extracellular traps induced by IL-8 aggravate atherosclerosis via activation NF-κB signaling in macrophages

An¹,

et al. 2019

Cell Cycle

175

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“…It has also been reported to be able to promote the differentiation of T helper 1 cells [10]. Studies using small interfering RNAs to knockdown expression of TMEM98 have pointed to it having a role in the invasion and migration of lung cancer cells and in atherosclerosis [11,12] and it may also be important for wound healing [13]. TMEM98 was one of a set of genes used to construct a developmental hierarchy of breast cancer cells which could inform treatment strategies and disease prognosis [14].…”

Section: Introductionmentioning

confidence: 99%

The nanophthalmos protein TMEM98 inhibits MYRF self-cleavage and is required for eye size specification

et al. 2020

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The precise control of eye size is essential for normal vision. TMEM98 is a highly conserved and widely expressed gene which appears to be involved in eye size regulation. Mutations in human TMEM98 are found in patients with nanophthalmos (very small eyes) and variants near the gene are associated in population studies with myopia and increased eye size. As complete loss of function mutations in mouse Tmem98 result in perinatal lethality, we produced mice deficient for Tmem98 in the retinal pigment epithelium (RPE), where Tmem98 is highly expressed. These mice have greatly enlarged eyes that are very fragile with very thin retinas, compressed choroid and thin sclera. To gain insight into the mechanism of action we used a proximity labelling approach to discover interacting proteins and identified MYRF as an interacting partner. Mutations of MYRF are also associated with nanophthalmos. The protein is an endoplasmic reticulum-tethered transcription factor which undergoes autoproteolytic cleavage to liberate the N-terminal part which then translocates to the nucleus where it acts as a transcription factor. We find that TMEM98 inhibits the self-cleavage of MYRF, in a novel regulatory mechanism. In RPE lacking TMEM98, MYRF is ectopically activated and abnormally localised to the nuclei. Our findings highlight the importance of the interplay between TMEM98 and MYRF in determining the size of the eye.

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“…As miRNA molecules serve diverse biological roles with multiple targets, they have become novel candidates for the diagnosis and treatment of diseases (14). MiRNAs are involved in a majority of pathophysiological processes and they are associated to vascular endothelial cell damages in two aspects (15,16). The first aspect describes a decreased ability to repair endothelial cell damage and is characterized by inhibited proliferation and migration of cells (15).…”

Section: Introductionmentioning

confidence: 99%

“…MiRNAs are involved in a majority of pathophysiological processes and they are associated to vascular endothelial cell damages in two aspects (15,16). The first aspect describes a decreased ability to repair endothelial cell damage and is characterized by inhibited proliferation and migration of cells (15). The second aspect describes endothelial dysfunction, characterized by abnormal secretion of vascular endothelial cell factors (16).…”

Section: Introductionmentioning

confidence: 99%

Reduced expression of microRNA‑199a‑3p is associated with vascular endothelial cell injury induced by type 2 diabetes mellitus

Wang

Tang

2018

Exp Ther Med

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The aim of the present study was to investigate the function and mechanism of action of microRNA (miRNA or miR)-199a-3p in vascular endothelial cell injury induced by type 2 diabetes mellitus (T2DM). A total of 36 patients with T2DM (26 males and 10 females; mean age, 52.5±7.0 years) and 20 healthy subjects (10 males and 10 females; mean age, 55.6±4.5 years) were included in the present study. Peripheral blood samples were obtained from all participants and total RNA was extracted Reverse transcription-quantitative polymerase chain reaction was performed to determine the expression of miR-199a-3p. Following the transfection of human umbilical vein endothelial cells (HUVECs) with a negative control (NC) miRNA or miR-199a-3p mimics, cell proliferation was assessed using a Cell Counting kit-8 assay. Cell migration was investigated using Transwell assays and flow cytometry was performed to detect the apoptosis of HUVECs. HUVECs were infected with Ad-GFP-LC3B and laser-scanning confocal microscopy was performed to observe autophagosomes in HUVECs. Western blotting was used to measure the expression of proteins associated with autophagy and the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/nuclear factor (NF)-κB signaling pathway. MiR-199a-3p was downregulated in peripheral blood from patients with T2DM compared with healthy subjects. Transfection with miR-199a-3p mimics promoted the proliferation and migration of HUVECs. However, miR-199a-3p overexpression inhibited the apoptosis of HUVECs. MiR-199a-3p facilitated HUVEC autophagy by affecting autophagy-associated signaling pathways. Furthermore, miR-199a-3p regulated the biological functions of HUVECs via the PI3K/AKT/NF-κB signaling pathway. The results of the present study suggest that miR-199a-3p expression was reduced in patients with T2DM compared with healthy subjects and may be associated with vascular endothelial cell injury. In addition, miR-199a-3p promoted the proliferation, migration and autophagy of HUVECs, potentially by regulating the PI3K/AKT/NF-κB signaling pathway. Therefore, miR-199a-3p may function as protector of vascular endothelia.

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Inhibition of IL-8-mediated endothelial adhesion, VSMCs proliferation and migration by siRNA-TMEM98 suggests TMEM98's emerging role in atherosclerosis

Cited by 18 publications

References 34 publications

Neutrophil extracellular traps induced by IL-8 aggravate atherosclerosis via activation NF-κB signaling in macrophages

Neutrophil extracellular traps induced by IL-8 aggravate atherosclerosis via activation NF-κB signaling in macrophages

The nanophthalmos protein TMEM98 inhibits MYRF self-cleavage and is required for eye size specification

Reduced expression of microRNA‑199a‑3p is associated with vascular endothelial cell injury induced by type 2 diabetes mellitus

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