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Myricetin ameliorates ox-LDL-induced HUVECs apoptosis and inflammation via lncRNA GAS5 upregulating the expression of miR-29a-3p.

ABSTRACT: Oxidized low-density lipoprotein (ox-LDL)-induced endothelial cell dysfunction is a significant event in the progression of atherosclerosis. Even Myricetin (Myr) has been exhibited strong antioxidant potency, the effect on atherosclerosis is still elusive. HUVECs were subjected to ox-LDL, before which cells were preconditioned with Myr. Cell Counting Kit-8 assay, flow cytometry, quantitative real-time polymerase chain reaction and Western blot were carried out to assess the impacts of ox-LDL and Myr on HUVECs. The expression of EndMT markers was determined by Western blot analysis and immunocytochemistry. In addition, the relationship of GAS5 and miR-29a-3p was evaluated by RNA Fluorescent in Situ Hybridization and RNA immunoprecipitation assay. Myr preconditioning prevented ox-LDL-induced apoptosis, inflammatory response, and EndMT. GAS5 was upregulated in response to ox-LDL while it was down-regulated by Myr preconditioning. GAS5 over-expression attenuates Myr protective effects against ox-LDL-mediated HUVEC injury. Besides, miR-29a-3p is a target of GAS5 and down-regulated miR-29a-3p could further reduce the effects of GAS5 in ox-LDL-mediated HUVEC. Furthermore, Myr inactivated the TLR4/NF-κB signalling pathway in ox-LDL-treated HUVEC by down-regulating GAS5 or upregulating miR-26a-5p. Myr possessed an anti-inflammatory and anti-EndMT function against ox-LDL-induced HUVEC injury by regulating the GAS5/miR-29a-3p, indicating that Myr may have an important therapeutic function for atherosclerosis.

SUBMITTER: Bai Y

PROVIDER: S-EPMC8490408 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Objective: Angiogenesis is involved in multiple biological processes, including atherosclerosis (AS) and cancer. Dickkopf1 (DKK1) plays many roles in both tumors and AS and has emerged as a potential biomarker of cancer progression and prognosis. Targeting DKK1 is a good choice for oncological treatments. Many anticancer therapies are associated with specific cardiovascular toxicity. However, the effects of DKK1 neutralizing therapy on AS are unclear. We focused on how DKK1 affected angiogenesis in AS and ox-LDL-induced human umbilical vein endothelial cells (HUVECs). Methods: ApoE-/- mice were fed a high-fat diet and then injected with DKK1i or DKK1 lentivirus to study the effects of DKK1. In vitro, promoter assays, protein analysis, database mining, dual-luciferase reporter assay (DLR), electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), and coimmunoprecipitation (co-IP) were used to study the mechanism of DKK1 biogenesis. Cell migration and angiogenesis assays were performed to investigate the function and regulatory mechanisms of DKK1. Results: DKK1 participated in angiogenesis both in the plaques of ApoE-/- mice by knockdown or overexpression of DKK1 and ox-LDL-induced HUVECs. DKK1 induced angiogenesis (increasing migration and capillary formation, inducing expression of VEGFR-2/VEGF-A/MMP) via the CKAP4/PI3K pathway, independent of Wnt/β-catenin. ox-LDL increased the expression and nuclear transfer of Ets-1 and c-jun, and induced the transcriptional activity of DKK1 in HUVECs. Ets-1, along with c-jun and CBP, could bind to the promoter of DKK1 and enhance DKK1 transcription. MiR33a-5p was downregulated in ox-LDL induced HUVECs and aortic artery of high-fat diet ApoE-/- mice. Ets-1 was a direct target of miR33a-5p. MiR33a-5p/Ets-1/ DKK1 axis contributed to angiogenesis. Conclusions: MiR33a-5p/Ets-1/DKK1 signaling participated in ox-LDL-induced angiogenesis of HUVECs via the CKAP4/PI3K pathway. These new findings provide a rationale and notable method for tumor therapy and cardiovascular protection.

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Myricetin ameliorates ox-LDL-induced HUVECs apoptosis and inflammation via lncRNA GAS5 upregulating the expression of miR-29a-3p.

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