title: Ligation of ICAM-1 on human aortic valve interstitial cells induces the osteogenic response: A critical role of the Notch1-NF-κB pathway in BMP-2 expression.
abstract: Calcific aortic valve disease (CAVD) is a chronic inflammatory condition and affects a large number of elderly people. Aortic valve interstitial cells (AVICs) occupy an important role in valvular calcification and CAVD progression. While pro-inflammatory mechanisms are capable of inducing the osteogenic responses in AVICs, the molecular interaction between pro-inflammatory and pro-osteogenic mechanisms remains poorly understood. This study tested the hypothesis that intercellular adhesion molecule-1 (ICAM-1) plays a role in mediating pro-osteogenic factor expression in human AVICs. AVICs were isolated from normal human aortic valves and cultured in M199 medium. Treatment with leukocyte function-associated factor-1 (LFA-1, an ICAM-1 ligand) up-regulated the expression of bone morphogenetic protein-2 (BMP-2) and resulted in increased alkaline phosphatase activity and formation of calcification nodules. Pre-treatment with lipopolysaccharide (LPS, 0.05μg/ml) increased ICAM-1 levels on cell surfaces and exaggerated the pro-osteogenic response to LFA-1, and neutralization of ICAM-1 suppressed this response. Further, ligation of ICAM-1 by antibody cross-linking also up-regulated BMP-2 expression. Interestingly, LFA-1 elicited Notch1 cleavage and NF-κB activation. Inhibition of NF-κB markedly reduced LFA-1-induced BMP-2 expression, and inhibition of Notch1 cleavage with a γ-secretase inhibitor suppressed LFA-1-induced NF-κB activation and BMP-2 expression. Ligation of ICAM-1 on human AVICs activates the Notch1 pathway. Notch1 up-regulates BMP-2 expression in human AVICs through activation of NF-κB. The results demonstrate a novel role of ICAM-1 in translating a pro-inflammatory signal into a pro-osteogenic response in human AVICs and suggest that ICAM-1 on the surfaces of AVICs contributes to the mechanism of aortic valve calcification.
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, CO 80045, USA; Department of Anatomy, The Second Military Medical University, Shanghai, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, CO 80045, USA; Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Qingchun
authors.initials: Q
authors.lastname: Zeng
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, CO 80045, USA; Department of Pathophysiology, Southern Medical University, Guangzhou, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Song
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Lihua
authors.initials: L
authors.lastname: Ao
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Fullerton
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, CO 80045, USA. Electronic address: xianzhong.meng@ucdenver.edu.
authors.forename: Xianzhong
authors.initials: X
authors.lastname: Meng
keywords: Aortic valve; ICAM-1; Notch1; Pro-osteogenic response; Signal transduction
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