title: Interleukin-37 suppresses the osteogenic responses of human aortic valve interstitial cells in vitro and alleviates valve lesions in mice.
abstract: 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.
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, CO 80045.|Department of Cardiology, Southern Medical University, Guangzhou, China 510515.
authors.forename: Qingchun
authors.initials: Q
authors.lastname: Zeng
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, CO 80045.|Department of Pathophysiology, Southern Medical University, Guangzhou, China 510515.
authors.forename: Rui
authors.initials: R
authors.lastname: Song
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, CO 80045.
authors.forename: David A
authors.initials: DA
authors.lastname: Fullerton
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, CO 80045.
authors.forename: Lihua
authors.initials: L
authors.lastname: Ao
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, CO 80045.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Zhai
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, CO 80045.
authors.forename: Suzhao
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Medicine, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Dov B
authors.initials: DB
authors.lastname: Ballak
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, CO 80045.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Cleveland
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, CO 80045.
authors.forename: T Brett
authors.initials: TB
authors.lastname: Reece
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, CO 80045.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: McKinsey
authors.affiliation: Department of Cardiology, Southern Medical University, Guangzhou, China 510515; xianzhong.meng@ucdenver.edu cdinare333@aol.com dinglixu@fimmu.com.
authors.forename: Dingli
authors.initials: D
authors.lastname: Xu
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, CO 80045; xianzhong.meng@ucdenver.edu cdinare333@aol.com dinglixu@fimmu.com.|Department of Medicine, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, CO 80045; xianzhong.meng@ucdenver.edu cdinare333@aol.com dinglixu@fimmu.com.
authors.forename: Xianzhong
authors.initials: X
authors.lastname: Meng
mesh_terms: D000368:Aged; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001021:Aortic Valve / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001024:Aortic Valve Stenosis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism; D002114:Calcinosis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects*; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D055396:Bone Morphogenetic Protein 2; D007378:Interleukins; D016328:NF-kappa B; D011994:Recombinant Proteins; D000469:Alkaline Phosphatase
keywords: Toll-like receptors; calcification; inflammation; oxidized low-density lipoprotein; signal transduction