PMID- 32892299 OWN - NLM STAT- MEDLINE DCOM- 20210603 LR - 20210603 IS - 1573-4978 (Electronic) IS - 0301-4851 (Print) IS - 0301-4851 (Linking) VI - 47 IP - 9 DP - 2020 Sep TI - Acacetin improves endothelial dysfunction and aortic fibrosis in insulin-resistant SHR rats by estrogen receptors. PG - 6899-6918 LID - 10.1007/s11033-020-05746-3 [doi] AB - The aim of the work was to investigate the effects of acacetin on endothelial dysfunction and aortic fibrosis in insulin-resistant SHR rats and explore its mechanism. Seven-week-old male spontaneously hypertensive rats (SHR) were selected to establish a rat model of hypertension with insulin resistance induced by 10% fructose. The nuclear factor kappa B p65 (NF-kappaB p65) and Collagen I were observed by Immunohistochemistry. Immunofluorescence was used to observe estrogen receptor-alpha (ERalpha), estrogen receptor-beta (ERbeta), and G protein-coupled receptor 30 (GPR30). Western blotting was used to detect interleukin (IL-1beta), Arginase 2 (ARG2), Nostrin, endothelial nitric oxide synthase (eNOS), TGF-beta, Smad3, ERK pathway proteins such as p-c-Raf, p-MEK1/2, p-ERK, ERK, p-P90RSK and p-MSK1. We found that acacetin did have an improvement on endothelial dysfunction and fibrosis. Meanwhile, it was also found to have a significant effect on the level of estrogen in this model by accident. Then, the experiment of uterine weight gain in mice confirmed that acacetin had a certain estrogen-like effect in vivo and played its role through the estrogen receptors pathway. In vitro experience HUVEC cells were stimulated with 30 mM/L glucose and 100 mM/L NaCl for 24 h to establish the endothelial cell injury model. HUVEC cells were treated with 1 muM/L estrogen receptors antagonist (ICI 182780) for 30 min before administration. Cell experiments showed that acacetin could reduce the apoptosis of HUVEC cells, the levels of inflammatory cytokines and the expression of TGF-beta, Collagen I and Smad3 in endothelial cell injury model. After treatment with ICI 182780, the improvement of acacetin was significantly reversed. The results showed that acacetin relieved endothelial dysfunction and reduced the aortic fibrosis in insulin-resistant SHR rats by reducing the release of inflammatory factors and improving vasodilatory function through estrogen signaling pathway. FAU - Wei, Yaxin AU - Wei Y AD - Henan University of Chinese Medicine, Zhengzhou, 450046, China. FAU - Yuan, Peipei AU - Yuan P AD - Henan University of Chinese Medicine, Zhengzhou, 450046, China. FAU - Zhang, Qi AU - Zhang Q AD - Henan University of Chinese Medicine, Zhengzhou, 450046, China. FAU - Fu, Yang AU - Fu Y AD - Henan University of Chinese Medicine, Zhengzhou, 450046, China. FAU - Hou, Ying AU - Hou Y AD - Henan University of Chinese Medicine, Zhengzhou, 450046, China. FAU - Gao, Liyuan AU - Gao L AD - Henan University of Chinese Medicine, Zhengzhou, 450046, China. FAU - Zheng, Xiaoke AU - Zheng X AUID- ORCID: 0000-0003-3671-231X AD - Henan University of Chinese Medicine, Zhengzhou, 450046, China. zhengxk.2006@163.com. FAU - Feng, Weisheng AU - Feng W AD - Henan University of Chinese Medicine, Zhengzhou, 450046, China. fwsh@hactcm.edu.cn. LA - eng GR - 2017YFC1702800/The Major Project for Research of the Modernization of TCM/ GR - 2019YFC1708802/The Major Project for Research of the Modernization of TCM/ GR - ZYQR201810080/Henan province high-level personnel special support "ZhongYuan One Thousand People Plan"-Zhongyuan Leading Talent/ PT - Journal Article DEP - 20200906 PL - Netherlands TA - Mol Biol Rep JT - Molecular biology reports JID - 0403234 RN - 0 (Collagen Type I) RN - 0 (Flavones) RN - 0 (Gper1 protein, rat) RN - 0 (IL1B protein, rat) RN - 0 (Interleukin-1beta) RN - 0 (NF-kappa B) RN - 0 (Receptors, Estrogen) RN - 0 (Receptors, G-Protein-Coupled) RN - 0 (Transforming Growth Factor beta) RN - 451W47IQ8X (Sodium Chloride) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type III) RN - EC 1.14.13.39 (Nos3 protein, rat) RN - EC 3.5.3.1 (Arg2 protein, rat) RN - EC 3.5.3.1 (Arginase) RN - IY9XDZ35W2 (Glucose) RN - KWI7J0A2CC (acacetin) SB - IM MH - Animals MH - Aorta/*drug effects/pathology MH - Apoptosis/drug effects MH - Arginase/metabolism MH - Collagen Type I/metabolism MH - Endothelial Cells/*drug effects/metabolism MH - Fibrosis/*drug therapy MH - Flavones/*pharmacology MH - Glucose/*pharmacology MH - Human Umbilical Vein Endothelial Cells MH - Humans MH - Immunohistochemistry MH - Insulin Resistance MH - Interleukin-1beta/metabolism MH - MAP Kinase Signaling System/drug effects MH - Male MH - NF-kappa B/metabolism MH - Nitric Oxide Synthase Type III/metabolism MH - Rats MH - Rats, Inbred SHR MH - Receptors, Estrogen/antagonists & inhibitors/*metabolism MH - Receptors, G-Protein-Coupled/metabolism MH - Sodium Chloride/pharmacology MH - Transforming Growth Factor beta/metabolism PMC - PMC7561596 OTO - NOTNLM OT - Acacetin OT - Aortic fibrosis OT - Endothelial dysfunction OT - Estrogen receptors EDAT- 2020/09/07 06:00 MHDA- 2021/06/04 06:00 PMCR- 2020/09/06 CRDT- 2020/09/06 20:36 PHST- 2020/05/08 00:00 [received] PHST- 2020/08/28 00:00 [accepted] PHST- 2020/09/07 06:00 [pubmed] PHST- 2021/06/04 06:00 [medline] PHST- 2020/09/06 20:36 [entrez] PHST- 2020/09/06 00:00 [pmc-release] AID - 10.1007/s11033-020-05746-3 [pii] AID - 5746 [pii] AID - 10.1007/s11033-020-05746-3 [doi] PST - ppublish SO - Mol Biol Rep. 2020 Sep;47(9):6899-6918. doi: 10.1007/s11033-020-05746-3. Epub 2020 Sep 6.