PMID- 32573820 OWN - NLM STAT- MEDLINE DCOM- 20210209 LR - 20210209 IS - 1938-3673 (Electronic) IS - 0741-5400 (Print) IS - 0741-5400 (Linking) VI - 108 IP - 6 DP - 2020 Dec TI - Aloe emodin relieves Ang II-induced endothelial junction dysfunction via promoting ubiquitination mediated NLRP3 inflammasome inactivation. PG - 1735-1746 LID - 10.1002/JLB.3MA0520-582R [doi] AB - Recent studies have revealed that aloe emodin (AE), a natural compound from the root and rhizome of Rheum palmatum L., exhibits significant pharmacologic activities. However, the pharmacologic relevance of the compound, particularly for cardiovascular disease, remains largely unknown. Here, we hypothesized that AE could improve endothelial junction dysfunction through inhibiting the activation of NOD-like receptor family pyrin domain containing-3 (NLRP3) inflammasome regulated by NLRP3 ubiquitination, and ultimately prevent cardiovascular disease. In vivo, we used confocal microscopy to study the expression of tight junction proteins zonula occludens-1/2 (ZO-1/2) and the formation of NLRP3 inflammasome in coronary arteries of hypertension. And the experimental serum was used to detect the activation of NLRP3 inflammasome by ELISA assay. We found that AE could restore the expression of the endothelial connective proteins ZO-1/2 and decrease the release of high mobility group box1 (HMGB1), and also inhibited the formation and activation of NLRP3 inflammasome. Similarly, in vitro, our findings demonstrated that AE could restore the expression of the tight junction proteins ZO-1/2 and decrease monolayer cell permeability that related to endothelial function after stimulation by angiotensin II (Ang II) in microvascular endothelial cells (MECs). We also demonstrated that AE could inhibit Ang II-induced NLRP3 inflammasome formation and activation, which were regulated by NLRP3 ubiquitination in MECs, as shown by fluorescence confocal microscopy and Western blot. Together with these changes, we revealed a new protection mechanism of AE that inhibited NLRP3 inflammasome activation and decreased the release of HMGB1 by promoting NLRP3 ubiquitination. Our findings implicated that AE exhibited immense potential and specific therapeutic value in hypertension-related cardiovascular disease in the early stage and the development of innovative drugs. CI - (c) 2020 Amgen Inc. Journal of Leukocyte Biology published by Wiley Periodicals LLC on behalf of Society for Leukocyte Biology. FAU - Zhang, Yi AU - Zhang Y AD - School of Pharmaceutical, Guangzhou University of Chinese Medicine, Guangzhou University Town, Guangzhou, China. FAU - Song, Ziqing AU - Song Z AD - School of Pharmaceutical, Guangzhou University of Chinese Medicine, Guangzhou University Town, Guangzhou, China. FAU - Huang, Shan AU - Huang S AD - Department of Stomatology, The First Affiliated Hospital, The School of Dental Medicine, Jinan University, Guangzhou, China. FAU - Zhu, Li AU - Zhu L AD - School of Pharmaceutical, Guangzhou University of Chinese Medicine, Guangzhou University Town, Guangzhou, China. FAU - Liu, Tianyi AU - Liu T AD - School of Pharmaceutical, Guangzhou University of Chinese Medicine, Guangzhou University Town, Guangzhou, China. FAU - Shu, Hongyan AU - Shu H AD - School of Pharmaceutical, Guangzhou University of Chinese Medicine, Guangzhou University Town, Guangzhou, China. FAU - Wang, Lei AU - Wang L AD - School of Pharmaceutical, Guangzhou University of Chinese Medicine, Guangzhou University Town, Guangzhou, China. FAU - Huang, Yi AU - Huang Y AD - Department of Stomatology, The First Affiliated Hospital, The School of Dental Medicine, Jinan University, Guangzhou, China. FAU - Chen, Yang AU - Chen Y AUID- ORCID: 0000-0003-0206-1889 AD - School of Pharmaceutical, Guangzhou University of Chinese Medicine, Guangzhou University Town, Guangzhou, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200623 PL - England TA - J Leukoc Biol JT - Journal of leukocyte biology JID - 8405628 RN - 0 (Anthraquinones) RN - 0 (HMGB1 Protein) RN - 0 (HMGB1 protein, human) RN - 0 (Inflammasomes) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (Nlrp3 protein, mouse) RN - 0 (Tjp1 protein, mouse) RN - 0 (Tjp2 protein, mouse) RN - 0 (Zonula Occludens-1 Protein) RN - 0 (Zonula Occludens-2 Protein) RN - 11128-99-7 (Angiotensin II) RN - C8IYT9CR7C (aloe emodin) SB - IM MH - Angiotensin II/*adverse effects/pharmacology MH - Animals MH - Anthraquinones/*pharmacology MH - Endothelial Cells/*immunology/pathology MH - HMGB1 Protein/immunology MH - Inflammasomes/*immunology MH - Male MH - Mice MH - NLR Family, Pyrin Domain-Containing 3 Protein/*immunology MH - Tight Junctions/*immunology/pathology MH - Ubiquitination/*drug effects/immunology MH - Zonula Occludens-1 Protein/immunology MH - Zonula Occludens-2 Protein/immunology PMC - PMC7754316 OTO - NOTNLM OT - Aloe emodin OT - Ang II OT - NLRP3 inflammasome OT - NLRP3 ubiquitination OT - endothelial dysfunction COIS- The authors declare no conflicts of interest. EDAT- 2020/06/24 06:00 MHDA- 2021/02/10 06:00 PMCR- 2020/12/22 CRDT- 2020/06/24 06:00 PHST- 2019/11/04 00:00 [received] PHST- 2020/05/06 00:00 [revised] PHST- 2020/05/26 00:00 [accepted] PHST- 2020/06/24 06:00 [pubmed] PHST- 2021/02/10 06:00 [medline] PHST- 2020/06/24 06:00 [entrez] PHST- 2020/12/22 00:00 [pmc-release] AID - JLB10723 [pii] AID - 10.1002/JLB.3MA0520-582R [doi] PST - ppublish SO - J Leukoc Biol. 2020 Dec;108(6):1735-1746. doi: 10.1002/JLB.3MA0520-582R. Epub 2020 Jun 23.