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: Cristina M Alvira, Christophe Guignabert, Yu-Mee Kim, Chihhsin Chen, Lingli Wang, Trang T Duong, Rae S M Yeung, Dean Y Li, Marlene Rabinovitch
• Journal: The American journal of pathology (Am J Pathol) Vol. 178 Issue 3 Pg. 1210-20 (Mar 2011) ISSN: 1525-2191 [Electronic] United States
• PMID: 21356372 (Publication Type: Journal Article)
• Copyright: Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Collagen Type I
• Complex Mixtures
• Plasminogen Activator Inhibitor 1
• Transforming Growth Factor beta
• Tropoelastin
• Elastin
• Matrix Metalloproteinase 9

Topics

• Animals
• Cell Wall (chemistry)
• Collagen Type I (metabolism)
• Complex Mixtures
• Coronary Artery Disease (metabolism, pathology)
• Coronary Vessels (metabolism, pathology)
• Disease Models, Animal
• Elastin (metabolism)
• Lacticaseibacillus casei (chemistry)
• Matrix Metalloproteinase 9 (metabolism)
• Mice
• Mucocutaneous Lymph Node Syndrome (metabolism, pathology)
• Plasminogen Activator Inhibitor 1 (metabolism)
• Protein Processing, Post-Translational
• Signal Transduction
• Transforming Growth Factor beta (antagonists & inhibitors, metabolism)
• Tropoelastin (metabolism)