title: Inhibition of transforming growth factor β worsens elastin degradation in a murine model of Kawasaki disease.
abstract: Kawasaki disease (KD) is an acute inflammatory illness marked by coronary arteritis. However, the factors increasing susceptibility to coronary artery lesions are unknown. Because transforming growth factor (TGF) β increases elastin synthesis and suppresses proteolysis, we hypothesized that, in contrast to the benefit observed in aneurysms forming in those with Marfan syndrome, inhibition of TGF-β would worsen inflammatory-induced coronary artery lesions. By using a murine model of KD in which injection of Lactobacillus casei wall extract (LCWE) induces coronary arteritis, we show that LCWE increased TGF-β signaling in the coronary smooth muscle cells beginning at 2 days and continuing through 14 days, the point of peak coronary inflammation. By 42 days, LCWE caused fragmentation of the internal and external elastic lamina. Blocking TGF-β by administration of a neutralizing antibody accentuated the LCWE-mediated fragmentation of elastin and induced an overall loss of medial elastin without increasing the inflammatory response. We attributed these increased pathological characteristics to a reduction in the proteolytic inhibitor, plasminogen activator inhibitor-1, and an associated threefold increase in matrix metalloproteinase 9 activity compared with LCWE alone. Therefore, our data demonstrate that in the coronary arteritis associated with KD, TGF-β suppresses elastin degradation by inhibiting plasmin-mediated matrix metalloproteinase 9 activation. Thus, strategies to block TGF-β, used in those with Marfan syndrome, are unlikely to be beneficial and could be detrimental.
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305-5162, USA.
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Alvira
authors.forename: Christophe
authors.initials: C
authors.lastname: Guignabert
authors.forename: Yu-Mee
authors.initials: YM
authors.lastname: Kim
authors.forename: Chihhsin
authors.initials: C
authors.lastname: Chen
authors.forename: Lingli
authors.initials: L
authors.lastname: Wang
authors.forename: Trang T
authors.initials: TT
authors.lastname: Duong
authors.forename: Rae S M
authors.initials: RS
authors.lastname: Yeung
authors.forename: Dean Y
authors.initials: DY
authors.lastname: Li
authors.forename: Marlene
authors.initials: M
authors.lastname: Rabinovitch
mesh_terms: D000818:Animals; D002473:Cell Wall / Q000737:chemistry; D024042:Collagen Type I / Q000378:metabolism; D045424:Complex Mixtures; D003324:Coronary Artery Disease / Q000378:metabolism / Q000473:pathology; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004549:Elastin / Q000378:metabolism*; D007780:Lacticaseibacillus casei / Q000737:chemistry; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D009080:Mucocutaneous Lymph Node Syndrome / Q000378:metabolism* / Q000473:pathology*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014333:Tropoelastin / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D045424:Complex Mixtures; D017395:Plasminogen Activator Inhibitor 1; D016212:Transforming Growth Factor beta; D014333:Tropoelastin; D004549:Elastin; D020780:Matrix Metalloproteinase 9