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) ␤ 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-␤ 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-␤ 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-␤ 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-␤ suppresses elastin degradation by inhibiting plasmin-mediated matrix metalloproteinase 9 activation. Thus, strategies to block TGF-␤, used in those with Marfan syndrome, are unlikely to be beneficial and could be detrimental.

The role of TGF-β and myofibroblasts in the arteritis of Kawasaki disease

“…In a mouse model of coronary arteritis, TGF-β blockade resulted in increased elastin degradation associated with increased matrix metalloproteinase (MMP)-9 activity that resulted from TGF-β-mediated decrease in plasminogen activator inhibitor-1, an inhibitor of plasmin that activates MMP-9 [30]. Thus, caution must be excercised in drawing conclusions about the desirability of inhibiting TGF-β signaling in this patient population.…”

A cytokine axis regulates elastin formation and degradation

“…Indeed, TGFβ blockade exacerbates elastin degradation and decreases levels of elastin in medial layers of blood vessels (Alvira et al, 2011). By contrast, overexpression of a mutated, active form of TGFβ1 in animals having experimentally induced aortic aneurysms leads to reduction in the expression of elastolytic MMPs and preservation of elastic fibers in the medial layers of injured aortas (Dai et al, 2005).…”

Transforming growth factor beta signaling in adult cardiovascular diseases and repair

“…Unexpectedly, non-specific blocking of TGFβ by administration of TGFβNAb worsens the cardiovascular disease in these mice. This detrimental effect is attributed to a reduction in the proteolytic inhibitor and TGFβ target molecule, plasminogen activator inhibitor-1 (PAI1), and an associated increase in matrix metalloproteinase activity (Alvira et al 2011). It is noteworthy that many detrimental effects of TGFβ-based therapy can be attributed, in major part, to the role of TGFβ signaling in autoimmunity (Fig.…”

“…It is noteworthy that many detrimental effects of TGFβ-based therapy can be attributed, in major part, to the role of TGFβ signaling in autoimmunity (Fig. 3) (Yoshimura et al 2010;Shull et al 1992;Azhar et al 2009b;Anuurad et al 2011;Alvira et al 2011;King et al 2009;Tieu et al 2009;Daugherty et al 2010;Wang et al 2010;Mallat et al 2001). Consequently, although targeting TGFβ ligands and their signaling offers hope for treating valve, aortic and myocardial and inflammatory cardiovascular complications in both syndromic and non-syndromic patients, serious concerns remain whether a non-specific preemptive blocking of TGFβ ligands aimed to treat a single cardiovascular manifestation could result in undesirable side-effects on other aspects of cardiovascular remodeling or physiology.…”