title: Augmented osteogenic responses in human aortic valve cells exposed to oxLDL and TLR4 agonist: a mechanistic role of Notch1 and NF-κB interaction.
abstract: Aortic valve calcification causes the progression of calcific aortic valve disease (CAVD). Stimulation of aortic valve interstitial cells (AVICs) with lipopolysaccharide (LPS) up-regulates the expression of osteogenic mediators, and NF-κB plays a central role in mediating AVIC osteogenic responses to Toll-like receptor 4 (TLR4) stimulation. Diseased aortic valves exhibit greater levels of oxidized low-density lipoprotein (oxLDL). This study tested the hypothesis that oxLDL augments the osteogenic responses in human AVICs through modulation of NF-κB and Notch1 activation. AVICs isolated from normal human aortic valves were treated with LPS (0.1 µg/ml), oxLDL (20 µg/ml) or LPS plus oxLDL for 48 h. OxLDL alone increased cellular bone morphogenetic protein-2 (BMP-2) levels while it had no effect on alkaline phosphatase (ALP) levels. Cells exposed to LPS plus oxLDL produced higher levels of BMP-2 and ALP than cells exposed to LPS alone. Further, LPS plus oxLDL induced greater NF-κB activation, and inhibition of NF-κB markedly reduced the expression of BMP-2 and ALP in cells treated with LPS plus oxLDL. OxLDL also induced Notch1 activation and resulted in augmented Notch1 activation when it was combined with LPS. Inhibition of Notch1 cleavage attenuated NF-κB activation induced by LPS plus oxLDL, and inhibition of NF-κB suppressed the expression of BMP-2 and ALP induced by the synergistic effect of Jagged1 and LPS. These findings demonstrate that oxLDL up-regulates BMP-2 expression in human AVICs and synergizes with LPS to elicit augmented AVIC osteogenic responses. OxLDL exerts its effect through modulation of the Notch1-NF-κB signaling cascade. Thus, oxLDL may play a role in the mechanism underlying CAVD progression.
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, Colorado, United States of America; Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Qingchun
authors.initials: Q
authors.lastname: Zeng
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, Colorado, United States of America; Department of Pathophysiology, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Song
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Lihua
authors.initials: L
authors.lastname: Ao
authors.affiliation: Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Dingli
authors.initials: D
authors.lastname: Xu
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Neil
authors.initials: N
authors.lastname: Venardos
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: David A
authors.initials: DA
authors.lastname: Fullerton
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Xianzhong
authors.initials: X
authors.lastname: Meng
mesh_terms: D000368:Aged; D001021:Aortic Valve / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000082882:Bicuspid Aortic Valve Disease; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D002114:Calcinosis / Q000378:metabolism / Q000473:pathology; D009202:Cardiomyopathies / Q000378:metabolism / Q000473:pathology; D005260:Female; D006330:Heart Defects, Congenital / Q000378:metabolism / Q000473:pathology; D006349:Heart Valve Diseases / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects*; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000819:agonists*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D008070:Lipopolysaccharides; D008077:Lipoproteins, LDL; D016328:NF-kappa B; D051881:Receptor, Notch1; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C099252:oxidized low density lipoprotein