Notch1 Promotes the Pro-Osteogenic Response of Human Aortic Valve Interstitial Cells via Modulation of ERK1/2 and Nuclear Factor-κB Activation

Zeng, Qingchun; Song, Rui; Ao, Lihua; Weyant, Michael J.; Lee, Joon; Xu, Dingli; Fullerton, David A.; Meng, Xianzhong

doi:10.1161/atvbaha.112.300912

Cited by 71 publications

(92 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Further, IL-37 Tg mice exhibit reduced aortic valve thickening and BMP-2 levels after prolonged exposure to LPS or feeding with a high fat diet. Mechanistic data show that IL-37 suppresses the activation of NF-κB and ERK1/2, two important pathways that regulate BMP-2 and ALP expression in human AVICs (12,13). It should be noted that diseased aortic valve tissue is heterogeneous.…”

Section: Discussionmentioning

confidence: 99%

“…In this regard, proinflammatory mediators, such as tumor necrosis factor-α, have been shown to up-regulate the expression of osteogenic factor bone morphogenetic protein-2 (BMP-2) and early osteoblastic differentiation biomarker alkaline phosphatase (ALP) in AVICs (6, 7). We and others have observed that stimulation of either Toll-like receptor (TLR) 2 or TLR4 induces the osteogenic responses characterized by the expression of BMP-2 and ALP, among several other osteogenic biomarkers, in human AVICs (8)(9)(10)(11)(12), leading to the formation of calcification deposits in vitro (11)(12)(13). Moreover, bacteria associated with chronic periodontal infection and bacterial agents have been detected in diseased human aortic valves (14,15), and inoculation of rabbits with oral bacteria induces aortic valve lesions (16).…”

mentioning

confidence: 99%

“…AVICs of diseased aortic valves have augmented inflammatory and osteogenic responses to TLR2/4 agonists (11,12,17). It appears that an imbalance between proinflammatory and antiinflammatory mechanisms results in the disruption of valvular homeostasis, and such an imbalance may contribute to the mechanism underlying the development and progression of CAVD.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Interleukin-37 suppresses the osteogenic responses of human aortic valve interstitial cells in vitro and alleviates valve lesions in mice

Zeng

Song

Fullerton

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Calcific aortic valve disease is a chronic inflammatory process, and aortic valve interstitial cells (AVICs) from diseased aortic valves express greater levels of osteogenic factors in response to proinflammatory stimulation. Here, we report that lower cellular levels of IL-37 in AVICs of diseased human aortic valves likely account for augmented expression of bone morphogenetic protein-2 (BMP-2) and alkaline phosphatase (ALP) following stimulation of Toll-like receptor (TLR) 2 or 4. Treatment of diseased AVICs with recombinant human IL-37 suppresses the levels of BMP-2 and ALP as well as calcium deposit formation. In mice, aortic valve thickening is observed when exposed to a TLR4 agonist or a high fat diet for a prolonged period; however, mice expressing human IL-37 exhibit significantly lower BMP-2 levels and less aortic valve thickening when subjected to the same regimens. A high fat diet in mice results in oxidized low-density lipoprotein (oxLDL) deposition in aortic valve leaflets. Moreover, the osteogenic responses in human AVICs induced by oxLDL are suppressed by recombinant IL-37. Mechanistically, reduced osteogenic responses to oxLDL in human AVICs are associated with the ability of IL-37 to inhibit NF-κB and ERK1/2. These findings suggest that augmented expression of osteogenic factors in AVICs of diseased aortic valves from humans is at least partly due to a relative IL-37 deficiency. Because recombinant IL-37 suppresses the osteogenic responses in human AVICs and alleviates aortic valve lesions in mice exposed to high fat diet or a proinflammatory stimulus, IL-37 has therapeutic potential for progressive calcific aortic valve disease.Toll-like receptors | inflammation | oxidized low-density lipoprotein | calcification | signal transduction

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Interleukin-37 suppresses the osteogenic responses of human aortic valve interstitial cells in vitro and alleviates valve lesions in mice

Zeng

Song

Fullerton

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…In this regard, our previous studies demonstrated an important role of proinflammatory signaling pathways in mediating the osteogenic responses in human AVICs (13,20,29). Particularly, stimulation of TLR2 and TLR4 upregulates the expression of runt-related transcription factor, alkaline phosphatase and bone morphogenic protein-2 in human AVICs (29).…”

Section: Il-37 Inhibits Nf-jb Activation Mediated By Tlr2 and Tlr4mentioning

confidence: 91%

“…The MyD88-dependent pathway activates NF-κB and AP-1; the two transcription factors collectively regulate the expression of inflammatory mediators in most cell types (17). It has been demonstrated that the MyD88-mediated signaling pathway plays an important role in mediating tissue inflammation in many inflammation conditions, including myocardial ischemia-reperfusion injury (18), atherosclerosis (19) and cardiovascular calcification (20).…”

Section: Introductionmentioning

confidence: 99%

IL-37 Suppresses MyD88-mediated Inflammatory Responses in Human Aortic Valve Interstitial Cells

Zhan¹,

Zeng²,

Song³

et al. 2017

Mol Med

Self Cite

View full text Add to dashboard Cite

Calcific aortic valve disease (CAVD) is common among the elderly, and aortic valve interstitial cells (AVICs) exhibit unique inflammatory and osteogenic responses to proinflammatory stimulation, which plays an important role in valvular fibrosis and calcification. Thus, suppression of AVIC proinflammatory response may have therapeutic utility for the prevention of CAVD progression. Interleukin (IL)-37, an antiinflammatory cytokine, reduces tissue inflammation. This study aimed to test the hypothesis that IL-37 suppresses human AVIC inflammatory responses to Toll-like receptor (TLR) agonists. Human AVICs were exposed to Pam3CSK4, poly(I:C) and lipopolysaccharide in the presence and absence of recombinant human IL-37. Stimulation of TLR4 increased the production of intercellular adhesion molecule-1, IL-6, IL-8 and monocyte chemoattractant protein-1. Knockdown of myeloid differentiation factor 88 (MyD88) or TIR-domain-containing adaptor-inducing interferon-β differentially affected inflammatory mediator production following TLR4 stimulation. IL-37 reduced production of these inflammatory mediators induced by TLR4. Moreover, knockdown of IL-37 enhanced induction of these mediators by TLR4. IL-37 also suppressed inflammatory mediator production induced by the MyD88-dependent TLR2, but had no effect on the inflammatory responses to the TRIF-dependent TLR3. Furthermore, IL-37 inhibited NF-κB activation induced by TLR2 or TLR4 through a mechanism dependent of IL-18 receptor α-chain. Activation of TLR2, TLR3 or TLR4 upregulates the production of inflammatory mediators in human AVICs. IL-37 suppresses MyD88-mediated responses to reduce inflammatory mediator production following stimulation of TLR2 and TLR4. This antiinflammatory cytokine may be useful for suppression of aortic valve inflammation elicited by MyD88-dependent TLR signaling.

show abstract

Endothelial to mesenchymal transformation is induced by altered extracellular matrix in aortic valve endothelial cells

Dahal

Huang

Murray

et al. 2017

J Biomedical Materials Res

View full text Add to dashboard Cite

Alterations in shear stress, mechanical deformation, extracellular matrix (ECM) composition and exposure to inflammatory conditions are known to cause endothelial to mesenchymal transformation (EndMT). This change in endothelial phenotype has only recently been linked to adult pathologies such as cancer progression, organ fibrosis, and calcific aortic valve disease; and its function in adult physiology, especially in response to tissue mechanics, has not been rigorously investigated. EndMT is a response to mechanical and biochemical signals that results in the remodeling of underlying tissues. In diseased aortic valves, glycosaminoglycans (GAGs) are present in the collagen-rich valve fibrosa, and are deposited near calcified nodules. In this study, in vitro models of early and late-stage valve disease were developed by incorporating the GAGs chondroitin sulfate (CS), hyaluronic acid, and dermatan sulfate into 3D collagen hydrogels with or without exposure to TGF-β1 to simulate EndMT in response to microenvironmental changes. High levels of CS induced the highest rate of EndMT and led to the most collagen I and GAG production by mesenchymally transformed cells, which indicates a cell phenotype most likely to promote fibrotic disease. Mesenchymal transformation due to altered ECM was found to depend on cell-ECM bond strength and extracellular signal-regulated protein kinases 1/2 signaling. Determining the environmental conditions that induce and promote EndMT, and the subsequent behavior of mesenchymally transformed cells, will advance understanding on the role of endothelial cells in tissue regeneration or disease progression. © 2017 Wiley Periodicals Inc. J Biomed Mater Res Part A: 105A: 2729-2741, 2017.

show abstract

Notch1 Promotes the Pro-Osteogenic Response of Human Aortic Valve Interstitial Cells via Modulation of ERK1/2 and Nuclear Factor-κB Activation

Cited by 71 publications

References 31 publications

Interleukin-37 suppresses the osteogenic responses of human aortic valve interstitial cells in vitro and alleviates valve lesions in mice

Interleukin-37 suppresses the osteogenic responses of human aortic valve interstitial cells in vitro and alleviates valve lesions in mice

IL-37 Suppresses MyD88-mediated Inflammatory Responses in Human Aortic Valve Interstitial Cells

Endothelial to mesenchymal transformation is induced by altered extracellular matrix in aortic valve endothelial cells

Contact Info

Product

Resources

About