PMID- 34045591 OWN - NLM STAT- MEDLINE DCOM- 20211101 LR - 20240226 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 11 IP - 1 DP - 2021 May 27 TI - 5-LO-derived LTB4 plays a key role in MCP-1 expression in HMGB1-exposed VSMCs via a BLTR1 signaling axis. PG - 11100 LID - 10.1038/s41598-021-90636-2 [doi] LID - 11100 AB - Monocyte chemoattractant protein-1 (MCP-1) plays an important role in initiating vascular inflammation; however, its cellular source in the injured vasculatures is unclear. Given the importance of high mobility group box 1 (HMGB1) in tissue injury, we investigated the role of vascular smooth muscle cells (VSMCs) in MCP-1 production in response to HMGB1. In primary cultured rat aortic VSMCs stimulated with HMGB1, the expression of MCP-1 and 5-lipoxygenase (LO) was increased. The increased MCP-1 expression in HMGB1 (30 ng/ml)-stimulated cells was significantly attenuated in 5-LO-deficient cells as well as in cells treated with zileuton, a 5-LO inhibitor. Likewise, MCP-1 expression and production were also increased in cells stimulated with exogenous leukotriene B4 (LTB4), but not exogenous LTC4. LTB4-induced MCP-1 expression was attenuated in cells treated with U75302, a LTB4 receptor 1 (BLTR1) inhibitor as well as in BLTR1-deficient cells, but not in 5-LO-deficient cells. Moreover, HMGB1-induced MCP-1 expression was attenuated in BLTR1-deficient cells or by treatment with a BLTR1 inhibitor, but not other leukotriene receptor inhibitors. In contrast to MCP-1 expression in response to LTB4, the increased MCP-1 production in HMGB1-stimulated VSMC was markedly attenuated in 5-LO-deficient cells, indicating a pivotal role of LTB4-BLTR1 signaling in MCP-1 expression in VSMCs. Taken together, 5-LO-derived LTB4 plays a key role in MCP-1 expression in HMGB1-exposed VSMCs via BLTR1 signaling, suggesting the LTB4-BLTR1 signaling axis as a potential therapeutic target for vascular inflammation in the injured vasculatures. FAU - Choi, Jong Min AU - Choi JM AD - Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea. AD - Gene and Cell Therapy Research Center for Vessel-Associated Diseases, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea. FAU - Baek, Seung Eun AU - Baek SE AD - Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea. AD - Gene and Cell Therapy Research Center for Vessel-Associated Diseases, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea. FAU - Kim, Ji On AU - Kim JO AD - Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea. AD - Gene and Cell Therapy Research Center for Vessel-Associated Diseases, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea. FAU - Jeon, Eun Yeong AU - Jeon EY AD - Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea. AD - Gene and Cell Therapy Research Center for Vessel-Associated Diseases, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea. FAU - Jang, Eun Jeong AU - Jang EJ AD - Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea. AD - Gene and Cell Therapy Research Center for Vessel-Associated Diseases, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea. FAU - Kim, Chi Dae AU - Kim CD AD - Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea. chidkim@pusan.ac.kr. AD - Gene and Cell Therapy Research Center for Vessel-Associated Diseases, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea. chidkim@pusan.ac.kr. AD - Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Gyeongnam, 50612, Republic of Korea. chidkim@pusan.ac.kr. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210527 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 RN - 0 (Chemokine CCL2) RN - 0 (Fatty Alcohols) RN - 0 (Glycols) RN - 0 (HMGB1 Protein) RN - 119477-85-9 (U 75302) RN - 1HGW4DR56D (Leukotriene B4) RN - EC 1.13.11.34 (Arachidonate 5-Lipoxygenase) RN - V1L22WVE2S (zileuton) RN - X6Q56QN5QC (Hydroxyurea) SB - IM MH - Animals MH - Aorta/drug effects/metabolism MH - Arachidonate 5-Lipoxygenase/genetics/metabolism MH - Chemokine CCL2/*metabolism MH - Fatty Alcohols/pharmacology MH - Glycols/pharmacology MH - HMGB1 Protein/*pharmacology MH - Hydroxyurea/analogs & derivatives/pharmacology MH - Leukotriene B4/pharmacology MH - Mice, Knockout MH - Muscle, Smooth, Vascular/*drug effects/metabolism MH - Myocytes, Smooth Muscle/*drug effects/metabolism MH - Rats MH - Rats, Sprague-Dawley MH - Signal Transduction/*physiology MH - Mice PMC - PMC8160259 COIS- The authors declare no competing interests. EDAT- 2021/05/29 06:00 MHDA- 2021/11/03 06:00 PMCR- 2021/05/27 CRDT- 2021/05/28 06:58 PHST- 2020/08/21 00:00 [received] PHST- 2021/05/10 00:00 [accepted] PHST- 2021/05/28 06:58 [entrez] PHST- 2021/05/29 06:00 [pubmed] PHST- 2021/11/03 06:00 [medline] PHST- 2021/05/27 00:00 [pmc-release] AID - 10.1038/s41598-021-90636-2 [pii] AID - 90636 [pii] AID - 10.1038/s41598-021-90636-2 [doi] PST - epublish SO - Sci Rep. 2021 May 27;11(1):11100. doi: 10.1038/s41598-021-90636-2.