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MEK1/2 inhibitor reduces vascular calcification by regulating both canonical and non‐canonical Wnt signaling pathways
Author(s) -
Zeng Peng,
Yang Jie,
Liu Lipei,
Chen Yuanli,
Han Jihong
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.488.15
Subject(s) - wnt signaling pathway , calcification , osteopontin , lrp6 , dkk1 , runx2 , bone morphogenetic protein 2 , chemistry , signal transduction , microbiology and biotechnology , medicine , endocrinology , biology , cancer research , biochemistry , osteoblast , in vitro
We previously reported that MEK1/2 inhibitors, such as PD98059 or U0126, synergized liver X receptor (LXR) ligand, such as T0901317, activated macrophage ATP‐binding cassette transporter A1 (ABCA1) expression and free cholesterol efflux. Therefore, the combined U0126 and T0901317 can regress the established lesions. Additionally, U0126 increased lesion stability with unknown mechanisms. Vascular calcification is a major risk factor for plaque rupture. In this study, we determined if MEK1/2 inhibitors can affect atherosclerotic calcification and the underlying mechanisms. In vivo , we determined that treatment of apoE −/− mice with U0126 reduced HFD‐induced atherosclerotic calcification. It also reduced calcification medium‐induced calcium deposition in aortic rings ex vivo or in human aortic smooth muscle cells (HASMCs). Associated with reduction of vascular calcification, expression of osteogenic genes, such as bone morphogenetic protein 2 (BMP2), runt‐related transcription factor 2 (RUNX2), alkaline phosphatase (ALP), β‐catenin and osteopontin (OPN), were reduced by U0126, either in vivo or in vitro . Mechanistically, MEK1/2 inhibitors increased dickkopf 1 (DKK1) secretion and LDL receptor‐related protein 6 (LRP6) expression, thereby inhibiting canonical Wnt/β‐catenin signaling pathway while activating LRP6‐induced non‐canonical Wnt signaling pathway. In contrast, inactivation of either DKK1 or LRP6 attenuated the anti‐vascular calcification effects of MEK1/2 inhibitors. Based on the findings above, we conclude that MEK1/2 inhibitor can rescue vascular calcification through regulation of both canonical and non‐canonical Wnt signaling pathways. Our study also suggests inactivation of MER1/2 by chemicals can be a potential therapeutic strategy for treatment of atherosclerosis and atherosclerotic calcification. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .