PMID- 35194776 OWN - NLM STAT- MEDLINE DCOM- 20220617 LR - 20220718 IS - 1476-5381 (Electronic) IS - 0007-1188 (Linking) VI - 179 IP - 14 DP - 2022 Jul TI - Inhibition of chemically and mechanically activated Piezo1 channels as a mechanism for ameliorating atherosclerosis with salvianolic acid B. PG - 3778-3814 LID - 10.1111/bph.15826 [doi] AB - BACKGROUND AND PURPOSE: Salvianolic acid B (SalB) is effective for treating cardiovascular diseases. However, the molecular mechanisms underlying its therapeutic effects remain unclear. Mechanosensitive Piezo1 channels play important roles in vascular biology, although their pharmacological properties are poorly defined. Here, we aimed to identify novel Piezo1 inhibitors and gain insights into their mechanisms of action. EXPERIMENTAL APPROACH: Intracellular Ca(2+) ions were measured in HUVECs, murine liver endothelial cells (MLECs), THP-1 and RAW264.7 cell lines and bone marrow-derived macrophages (BMDMs). Isometric tensions in mouse thoracic aorta were recorded. Shear-stress assays with HUVECs were conducted. Patch-clamp recordings with mechanical stimulation were performed with HUVECs in whole-cell mode. Foam cell formation was induced by treating BMDMs with oxidised LDL (oxLDL). Atherosclerotic plaque assays were performed with Ldlr(-/-) and Piezo1 genetically depleted mice on a high-fat diet. KEY RESULTS: Salvianolic acid B inhibited Yoda1-induced Ca(2+) influx in HUVECs and MLECs. Similar results were observed in macrophage cell lines and BMDMs. Furthermore, we demonstrated that salvianolic acid B inhibited Yoda1- and mechanically activated currents. Salvianolic acid B suppressed Yoda1-induced aortic ring relaxation and inhibited HUVECs alignment in the direction of shear stress. Additionally, Yoda1 enhanced the formation of foam cells, which was reversed by salvianolic acid B. Salvianolic acid B also inhibited formation of atherosclerotic plaques and was insensitive to Piezo1 genetic depletion. CONCLUSION AND IMPLICATIONS: Our study provides novel mechanistic insights into the inhibitory role of salvianolic acid B against Piezo1 channels and improves our understanding of salvianolic acid B in preventing atherosclerotic lesions. CI - (c) 2022 The British Pharmacological Society. FAU - Pan, Xianmei AU - Pan X AD - The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China. AD - Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China. AD - The First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming, China. FAU - Wan, Rentao AU - Wan R AD - The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China. AD - Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China. FAU - Wang, Yuman AU - Wang Y AD - Medical Research Center, Shandong University of Chinese Medicine, Jinan, China. FAU - Liu, Silin AU - Liu S AD - The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China. AD - Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China. FAU - He, Yu AU - He Y AD - The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China. AD - Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China. FAU - Deng, Bo AU - Deng B AD - The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China. AD - Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China. FAU - Luo, Shangfei AU - Luo S AD - The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China. AD - Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China. FAU - Chen, Yuan AU - Chen Y AD - The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China. AD - Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China. FAU - Wen, Lizhen AU - Wen L AD - Medical Research Center, Shandong University of Chinese Medicine, Jinan, China. FAU - Hong, Tianying AU - Hong T AD - Medical Research Center, Shandong University of Chinese Medicine, Jinan, China. FAU - Xu, Han AU - Xu H AD - Medical Research Center, Shandong University of Chinese Medicine, Jinan, China. FAU - Bian, Yifei AU - Bian Y AD - Medical Research Center, Shandong University of Chinese Medicine, Jinan, China. FAU - Xia, Mingfeng AU - Xia M AD - Medical Research Center, Shandong University of Chinese Medicine, Jinan, China. FAU - Li, Jing AU - Li J AUID- ORCID: 0000-0002-0157-3041 AD - The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China. AD - Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China. AD - School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, UK. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220319 PL - England TA - Br J Pharmacol JT - British journal of pharmacology JID - 7502536 RN - 0 (Benzofurans) RN - 0 (Ion Channels) RN - 0 (Piezo1 protein, mouse) RN - C1GQ844199 (salvianolic acid B) SB - IM MH - Animals MH - *Atherosclerosis/drug therapy/metabolism MH - *Benzofurans/pharmacology MH - Endothelial Cells/metabolism MH - *Ion Channels/metabolism MH - Mice MH - RAW 264.7 Cells OTO - NOTNLM OT - Piezo1 channels OT - atherosclerosis OT - inhibitor OT - salvianolic acid B EDAT- 2022/02/24 06:00 MHDA- 2022/06/18 06:00 CRDT- 2022/02/23 05:36 PHST- 2022/01/30 00:00 [revised] PHST- 2021/06/21 00:00 [received] PHST- 2022/02/03 00:00 [accepted] PHST- 2022/02/24 06:00 [pubmed] PHST- 2022/06/18 06:00 [medline] PHST- 2022/02/23 05:36 [entrez] AID - 10.1111/bph.15826 [doi] PST - ppublish SO - Br J Pharmacol. 2022 Jul;179(14):3778-3814. doi: 10.1111/bph.15826. Epub 2022 Mar 19.