Although reduced ADAM17 mRNA expression in the liver of atherosclerosis resistant mice has been recently reported 7
, our data demonstrate a critical role of ADAM17 for neointimal hyperplasia in response to an arterial injury. In line with our observation of the enhanced ADAM17 expression in neointima, strong ADAM17 expression has been detected in intimal lesions of apoE−/− mice and human atherosclerotic plaque 8
. ADAM17 expression was also higher in patients with acute myocardial infarction than those with stable angina pectoris 9
. Moreover, single-nucleotide polymorphisms of ADAM17 are associated with increased serum tissue necrosis factor-α (TNFα) and the risk of cardiovascular death in patients with coronary artery disease 10
. Therefore, enhanced ADAM17 expression/activity could be a novel predictor of ongoing lesion formation in the vasculature.
EGFR activation has long been implicated in experimental models of restenosis 11–13
, however the mechanism through which this occurs in vivo
is ill defined. In this regard, there have been many mechanisms proposed to mediate EGFR activation associated with vascular remodeling including intracellular mechanisms without the participation of any EGFR ligand (whose precursor needs to be processed by a metalloprotease) 14
. As such, we believe our non-pharmacological data supporting a critical role for ADAM17 in EGFR activation leading to neointimal hyperplasia will move the field forward.
At present, the identity of the EGFR ligand(s) shed by ADAM17 responsible for the in vivo
EGFR activation remains unknown. ADAM17 is a major convertase of certain EGFR ligands including, heparin-binding EGF-like growth factor (HB-EGF), transforming growth factor-α, amphiregulin, and epiregulin in mouse embryonic cells 15
. In cultured VSMCs, HB-EGF has been reported to be responsible for EGFR transactivation and subsequent ERK activation induced by angiotensin II and other GPCR agonists 3, 16, 17
. Moreover, it has been reported that low flow-induced vascular remodeling was prevented in HB-EGF−/− mice 18
. Epiregulin produced by ADAM17 could also be involved in the neointimal hyperplasia. It is required for the EGFR transactivation and proliferation of VSMCs stimulated by fractalkine (CX3
. Moreover, epiregulin is a potent VSMC-derived mitogen induced by angiotensin II or endothelin 20
and is expressed in rat carotid artery after angioplasty and in human atherosclerotic arteries 21
. Likewise, there is the potential for ADAM17-dependent production of transforming growth factor-α and/or amphiregulin in mediating vascular neointima formation as they are both implicated in pathological vascular remodeling 22
. Therefore, it is likely that ADAM17 mediates EGFR transactivation in response to arterial injury through multiple EGFR ligands rather than through one single ligand.
In addition to the EGFR ligand precursors mentioned above, ADAM17 participates in the ectodomain shedding of over 40 cell surface proteins whose processing will produce mature cytokines/chemokines and other bioactive factors or lead to inactivation or modulation of the receptors or adhesion molecules 1, 23, 24
. Therefore, beside EGFR activation, other ADAM17-dependent shedding/modulation events may collaboratively contribute to the initiation and/or progression of the neointimal remodeling. For example, among the known ADAM17 substrates, the production of TNFα 25
, stem cell factor/kit ligand 27
, or macrophage colony-stimulating factor/CSF-1 28
, and inactivation of p75 TNF receptor-2 29
or p75 neurotrophin receptor 30
appear to be relevant for pathological vascular remodeling. Also, the effects of ADAM17 on various cell adhesion molecules should be considered 23
when trying to evaluate the mechanisms through which ADAM17 influences neointimal remodeling.
Limitations of the current study include the lack of identification of the responsible ADAM17 substrate(s) as mentioned above. Addressing this critical issue is expected to significantly advance knowledge about ADAM involvement within the cardiovascular system. Whilst ADAM substrate identification and involvement have been assessed in in vitro
experiments (biochemical assays with the recombinant protease and candidate substrates, reporter-based shedding assays in cultured cells, flow-cytometer to detect loss-of cell surface precursor, or culture medium detection of the cleaved products 31
), the list of ADAM17 substrates continues to grow. Indeed, recently developed “degradomics” approaches are anticipated to expand the list of potential substrates even further 31
. In combination, the sheer number of ADAM17 substrates that are likely to be involved, as well as a lack of technology to reliably measure ADAM17-dependent shedding in vivo
makes this question extremely difficult to resolve at present and may require the development of novel in vivo
measurement technology. In addition, the molecular mechanism by which ADAM17 is induced and activated in response to arterial injury awaits further investigations.
A potential contribution of ADAM17 to obesity and metabolic syndrome has been reported 32, 33
. ADAM17 is also implicated in hypertension, cardiac hypertrophy and fibrosis 34, 35
. Endothelial ADAM17 appears to be involved in pathological angiogenesis 36
. Our data presented here suggests that ADAM17 plays an important role in neointima formation following arterial injury and could be a novel therapeutic target against vascular remodeling associated with cardiovascular diseases. Further expansion of research is therefore expected to determine global as well as tissue specific roles of ADAM17 activity in regulating cardiovascular physiology and pathophysiology.