title: High mobility group box 1 induces calcification of aortic valve interstitial cells via toll-like receptor 4.
abstract: Chronic inflammation and the calcification of aortic valve interstitial cells (AVICs) are the primary etiologies of calcific aortic valve disease (CAVD). However, the underlying mechanism remains to be elucidated. The present study investigated the importance of high mobility group box 1 (HMGB1) via toll‑like receptor 4 (TLR4) for the regulation of inflammation and calcification in AVICs. It was determined that the expression levels of HMGB1 and TLR4 were increased in the calcific region of aortic valves with CAVD. In cultured primary AVICs from wild‑type mice, HMGB1 treatment demonstrated a dose-dependent increase in mineralization levels and osteogenic gene expression. These effects were significantly reduced in AVICs obtained from TLR4 knockout mice (TLR4‑/‑). In addition, calcification was inhibited by TLR4-specific antibodies in primary AVICs. HMGB1 induced the activation of p38 and nuclear factor-κB (NF-κB) in TLR4‑/‑ primary AVICs, and inhibited p38 and NF‑κB in wild‑type AVICs treated with TLR4‑specific antibodies. The present study demonstrated that TLR4 may function as an essential mediator of HMGB1‑induced calcification and in the activation of p38 and NF-κB.
authors.affiliation: Ningbo Medical Treatment Center, Lihuili Hospital, Ningbo, Zhejiang 310041, P.R. China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Shen
authors.affiliation: Ningbo Medical Treatment Center, Lihuili Hospital, Ningbo, Zhejiang 310041, P.R. China.
authors.forename: Jianqing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Ningbo Medical Treatment Center, Lihuili Hospital, Ningbo, Zhejiang 310041, P.R. China.
authors.forename: Chaoyang
authors.initials: C
authors.lastname: Wang
authors.affiliation: Ningbo Medical Treatment Center, Lihuili Hospital, Ningbo, Zhejiang 310041, P.R. China.
authors.forename: Guangze
authors.initials: G
authors.lastname: Xu
authors.affiliation: Ningbo Medical Treatment Center, Lihuili Hospital, Ningbo, Zhejiang 310041, P.R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Cardiovascular Disease, The Affiliated Tongji Hospital, Tongji University, Shanghai 210062, P.R. China.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Hu
mesh_terms: D000368:Aged; D000818:Animals; D001021:Aortic Valve / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D001024:Aortic Valve Stenosis / Q000378:metabolism / Q000473:pathology*; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D002114:Calcinosis / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D055396:Bone Morphogenetic Protein 2; D050659:Core Binding Factor Alpha 1 Subunit; D024243:HMGB1 Protein; D016328:NF-kappa B; D011994:Recombinant Proteins; D051197:Toll-Like Receptor 4; D048051:p38 Mitogen-Activated Protein Kinases