Inhibition of Transforming Growth Factor β Worsens Elastin Degradation in a Murine Model of Kawasaki Disease

Alvira, Cristina M.; Guignabert, Christophe; Kim, Yu Mee; Chen, Chih-Hsin; Wang, Lingli; Duong, Trang T.; Yeung, Rae S. M.; Li, Dean Y.; Rabinovitch, Marlene

doi:10.1016/j.ajpath.2010.11.054

Cited by 19 publications

(13 citation statements)

References 58 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2013

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Inflammation of medium-sized, muscular arteries and coronary artery aneurysms are hallmarks of Kawasaki disease (KD), an acute, self-limited vasculitis of children. We previously reported that genetic variation in transforming growth factor (TGF)-β pathway genes influences both susceptibility to KD and coronary artery aneurysm (CAA) formation. TGF-β signaling has been implicated in the generation of myofibroblasts that influence collagen lattice contraction, antigen presentation, and recruitment of inflammatory cells as well as the generation of regulatory T-cells (Tregs). These processes could be involved in aneurysm formation and recovery in KD. Coronary artery tissues from 8 KD patient autopsies were stained to detect proteins in the TGF-β pathway, to characterize myofibroblasts, and to detect Tregs. Expression of proteins in the TGF-β pathway was noted in infiltrating mononuclear cells and spindle-shaped cells in the thickened intima and adventitia. Coronary arteries from an infant who died on Illness Day 12 showed α-smooth muscle actin (SMA)-positive, smoothelin-negative myofibroblasts in the thickened intima that co-expressed IL-17 and IL-6. CD8+ T-cells expressing HLA-DR+ (marker of activation and proliferation) were detected in the aneurismal arterial wall. Forkhead box P3 (FOXP3), whose expression is essential for Tregs, was also detected in the nucleus of infiltrating mononuclear cells, suggesting a role for Tregs in recovery from KD arteritis. TGF-β may contribute to aneurysm formation by promoting the generation of myofibroblasts that mediate damage to the arterial wall through recruitment of pro-inflammatory cells. This multi-functional growth factor may also be involved in the induction of Tregs in KD.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2013

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“…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).…”

Section: Cytokines That Promote Elastin Formationmentioning

confidence: 99%

A cytokine axis regulates elastin formation and degradation

Sproul

Argraves

2013

Matrix Biology

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Underlying the dynamic regulation of tropoelastin expression and elastin formation in development and disease are transcriptional and post-transcriptional mechanisms that have been the focus of much research. Of particular importance is the cytokine–governed elastin regulatory axis in which the pro-elastogenic activities of transforming growth factor β-1 (TGFβ1) and insulin-like growth factor-I (IGF-I) are opposed by anti-elastogenic activities of basic fibroblast growth factor (bFGF/FGF-2), heparin-binding epidermal growth factor-like growth factor (HB-EGF), EGF, PDGF-BB, TGFα, tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β and noncanonical TGFβ1 signaling. A key mechanistic feature of the regulatory axis is that cytokines influence elastin formation through effects on the cell cycle involving control of cyclin–cyclin dependent kinase complexes and activation of the Ras/MEK/ERK signaling pathway. In this article we provide an overview of the major cytokines/growth factors that modulate elastogenesis and describe the underlying molecular mechanisms for their action on elastin production.

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“…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.…”

Section: Tgfβ-based Therapies and Its Potential Complications For Carmentioning

confidence: 99%

“…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.…”

Section: Tgfβ-based Therapies and Its Potential Complications For Carmentioning

confidence: 99%

Transforming growth factor beta signaling in adult cardiovascular diseases and repair

et al. 2011

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The majority of children with congenital heart disease now live into adulthood due to the remarkable surgical and medical advances that have taken place over the past half century. Because of this, the adults now represent the largest age group with adult cardiovascular diseases. They include patients with heart diseases that were not detected or not treated during childhood, those whose defects were surgically corrected but now need revision due to maladaptive responses to the procedure, those with exercise problems, and those with age-related degenerative diseases. Because adult cardiovascular diseases in this population are relatively new, they are not well understood. It is therefore necessary to understand the molecular and physiological pathways involved if we are to improve treatments. Since there is a developmental basis to adult cardiovascular disease, transforming growth factor beta (TGFβ) signaling pathways that are essential for proper cardiovascular development may also play critical roles in the homeostatic, repair and stress response processes involved in adult cardiovascular diseases. Consequently, we have chosen to summarize the current information on a subset of TGFβ ligand and receptor genes and related effector genes that when dysregulated are known to lead to cardiovascular diseases and adult cardiovascular deficiencies and/or pathologies. A better understanding of the TGFβ signaling network in cardiovascular disease and repair will impact genetic and physiologic investigations of cardiovascular diseases in elderly patients and lead to an improvement in clinical interventions.

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Inhibition of Transforming Growth Factor β Worsens Elastin Degradation in a Murine Model of Kawasaki Disease

Cited by 19 publications

References 58 publications

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

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

A cytokine axis regulates elastin formation and degradation

Transforming growth factor beta signaling in adult cardiovascular diseases and repair

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