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Your search keyword '"Zhang, L.C."' showing total 38 results
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38 results on '"Zhang, L.C."'

37. Cold-inducible RNA-binding protein but not its antisense lncRNA is a direct negative regulator of angiogenesis in vitro and in vivo via regulation of the 14q32 angiomiRs-microRNA-329-3p and microRNA-495-3p

Author

Goossens, E.A.C., Zhang, L.C., Vries, M.R. de, Jukema, J.W., Quax, P.H.A., and Nossent, A.Y.

Subjects
CIRBP, angiogenesis, 14q32 microRNAs, peripheral arterial disease, HUVECs
Abstract

Inhibition of the 14q32 microRNAs, miR-329-3p and miR-495-3p, improves post-ischemic neovascularization. Cold-inducible RNA-binding protein (CIRBP) facilitates maturation of these microRNAs. We hypothesized that CIRBP deficiency improves post-ischemic angiogenesis via downregulation of 14q32 microRNA expression. We investigated these regulatory mechanisms both in vitro and in vivo. We induced hindlimb ischemia in Cirp(-/-) and C57Bl/6-J mice, monitored blood flow recovery with laser Doppler perfusion imaging, and assessed neovascularization via immunohistochemistry. Post-ischemic angiogenesis was enhanced in Cirp(-/-) mice by 34.3% with no effects on arteriogenesis. In vivo at day 7, miR-329-3p and miR-495-3p expression were downregulated in Cirp(-/-) mice by 40.6% and 36.2%. In HUVECs, CIRBP expression was upregulated under hypothermia, while miR-329-3p and miR-495-3p expression remained unaffected. siRNA-mediated CIRBP knockdown led to the downregulation of CIRBP-splice-variant-1 (CIRBP-SV1), CIRBP antisense long noncoding RNA (lncRNA-CIRBP-AS1), and miR-495-3p with no effects on the expression of CIRBP-SV2-4 or miR-329-3p. siRNA-mediated CIRBP knockdown improved HUVEC migration and tube formation. SiRNA-mediated lncRNA-CIRBP-AS1 knockdown had similar long-term effects. After short incubation times, however, only CIRBP knockdown affected angiogenesis, indicating that the effects of lncRNA-CIRBP-AS1 knockdown were secondary to CIRBP-SV1 downregulation. CIRBP is a negative regulator of angiogenesis in vitro and in vivo and acts, at least in part, through the regulation of miR-329-3p and miR-495-3p.

Published
2021

38. METTL3 (Methyltransferase Like 3)-Dependent N6-Methyladenosine Modification on Braf mRNA Promotes Macrophage Inflammatory Response and Atherosclerosis in Mice.

Author

Li Q, Yu L, Gao A, Ren R, Zhang J, Cao L, Wang X, Liu Y, Qi W, Cai L, Li W, Wang W, Guo X, Su G, Yu X, Zhang J, Xi B, Zhang Y, Zhang M, and Zhang C

Subjects
Mice, Animals, Proto-Oncogene Proteins B-raf genetics, RNA, Messenger genetics, RNA, Messenger metabolism, Methyltransferases genetics, Methyltransferases metabolism, Macrophages metabolism, Inflammation genetics, Inflammation prevention & control, Inflammation metabolism, Apolipoproteins E metabolism, Plaque, Atherosclerotic metabolism, Atherosclerosis genetics, Atherosclerosis prevention & control, Atherosclerosis metabolism
Abstract

Background: Atherosclerosis is a chronic inflammatory disease, in which macrophages determine the progression of atherosclerotic plaques. However, no studies have investigated how METTL3 (methyltransferase like 3) in macrophages affects atherosclerotic plaque formation in vivo. Additionally, whether Braf mRNA is modified by METTL3-dependent N6-methyladenosine (m6A) methylation remains unknown., Methods: We analyzed single-cell sequencing data of atherosclerotic plaques in mice fed with a high fat diet for different periods. Mettl3 fl/fl Lyz 2 cre Apoe -/- mice and littermate control Mettl3 fl/fl Apoe -/- mice were generated and fed high fat diet for 14 weeks. In vitro, we stimulated peritoneal macrophages with ox-LDL (oxidized low-density lipoprotein) and tested the mRNA and protein expression levels of inflammatory factors and molecules regulating ERK (extracellular signal-regulated kinase) phosphorylation. To find METTL3 targets in macrophages, we performed m6A-methylated RNA immunoprecipitation sequencing and m6A-methylated RNA immunoprecipitation-qPCR. Further, point mutation experiments were used to explore m6A-methylated adenine. Using RNA immunoprecipitation assay, we explored m6A methylation-writing protein bound to Braf mRNA., Results: In vivo, METTL3 expression in macrophages increased with the progression of atherosclerosis. Myeloid cell-specific METTL3 deletion negatively regulated atherosclerosis progression and the inflammatory response. In vitro, METTL3 knockdown or knockout in macrophages attenuated ox-LDL-mediated ERK phosphorylation rather than JNK (c-Jun N-terminal kinase) and p38 phosphorylation and reduced the level of inflammatory factors by affecting BRAF protein expression. The negative regulation of inflammation response caused by METTL3 knockout was rescued by overexpression of BRAF. In mechanism, METTL3 targeted adenine (39725126 in chromosome 6) on the Braf mRNA. Then, YTHDF1 could bind to m6A-methylated Braf mRNA and promoted its translation., Conclusions: Myeloid cell-specific Mettl3 deficiency suppressed hyperlipidemia-induced atherosclerotic plaque formation and attenuated atherosclerotic inflammation. We identified Braf mRNA as a novel target of METTL3 in the activation of the ox-LDL-induced ERK pathway and inflammatory response in macrophages. METTL3 may represent a potential target for the treatment of atherosclerosis.

Published
2023
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