Abstract 1709: Transforming Growth Factor Beta Inhibition Increases Matrix Metalloproteinase-9 Activity and Enhances Elastin Degradation in a Murine Model of Kawasaki Disease
Background: Kawasaki disease (KD) is a leading cause of acquired heart disease in children. However, the molecular mechanisms leading to coronary aneurysms, and the host factors determining high-risk patients are unknown. We have previously shown that mice haploinsufficient for tropoelastin (EL ±), develop more severe destruction of the coronary elastin compared to wild type (WT) mice after injection with Lactobacillus casei wall extract (LCWE), an inducer of coronary arteritis. In contrast to the beneficial effect of TGFβ blockade on the aneurysms that form in Marfan syndrome (MS), we hypothesized that TGFβ protects against aneurysm formation in this inflammatory model by:
enhancing tropoelastin; and
suppressing proteolytic activity.
Methods: WT and EL ± mice were given either TGFβ neutralizing antibody (TGFβ-Nab) or control IgG in addition to LCWE. At 14d, tropoelastin and plasminogen activator inhibitor-1 (PAI-1) protein was determined, and matrix metalloproteinase (MMP)-2 and -9 and serine elastase activity was measured. Elastin degradation and total medial elastin content was assessed by morphometric analysis at 42d.
Results: TGFβ blockade worsened the LCWE-mediated fragmentation of the coronary elastin, with areas of complete dissolution of the external lamina in WT mice, and even more severe features in EL ± mice. Tropoelastin protein was 40% lower in the EL ± vs. WT mice after LCWE (P < 0.05), and TGFβ blockade further exaggerated this discrepancy. TGFβ-Nab markedly reduced PAI-1 in the WT mice after LCWE (P < 0.05), and produced a similar pattern in the EL ± mice, and induced a four-fold induction of MMP-9 activity in both genotypes. This effect was associated with increased elastin fragmentation (P < 0.05), and decreased total medial elastin content (P < 0.05), despite inhibition of the LCWE-mediated induction of serine elastase activity.
Conclusions: We conclude that:
diminished tropoelastin expression worsens elastin destruction in the setting of acute coronary arteritis; and
TGFβ protects the vasculature in this model by maintaining PAI-1 levels and suppressing activation of MMP-9.
Thus strategies to block TGFβ, currently in use to prevent aneurysms in MS, are unlikely to be beneficial in KD, and may be detrimental.
This research has received full or partial funding support from the American Heart Association, AHA National Center.