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Cardiovascular Research 1999 44(1):17-19; doi:10.1016/S0008-6363(99)00215-1
© 1999 by European Society of Cardiology
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Copyright © 1999, European Society of Cardiology

Is interleukin-1 beta a triggering factor for restenosis?

Barry S Oemar*

CuraGen Coorporation, 555 Long Wharf Drive, New Haven, CT 06511, USA

* Tel.: +1-203-401-3330, ext. 325; fax: +1-203-401-3337 boemar{at}curagen.com

Received 1 July 1999; accepted 1 July 1999

See article by Chamberlain et al. [9] (pages 156–165) in this issue.

Today, more than 20 years after percutaneous transluminal coronary angioplasty (PTCA) was introduced into the clinic by Andreas Grüntzig [1], PTCA has become a well-established and routine procedure for myocardial revascularization of patients with coronary heart disease (CHD). However, restenosis occurs in these patients at a rate between 30 and 50%, despite a successful initial procedure (for an extensive reviews see Refs. [2–5]). More than 60 large-scale clinical trials later, we are still struggling to understand why restenosis occurs in some but not in others, and why after 20 years the rate of restenosis is virtually unchanged, despite the availability of modern therapeutics and extensive knowledge in vascular biology [6–8]. The paper presented in this issue [9] intriguingly puts interleukin-1β (IL-1β) onto center stage as a possible triggering factor in the initiation process of restenosis, and may provide us with a handle for successful therapeutic intervention.

According to current concepts, three processes (phases) have been postulated to lead to post PTCA restenosis in patients [10]. Phase I is the acute lumen loss which occurs in some patients, and is termed elastic ‘recoil’. Recoil develops within hours of the intervention and appears to be the consequence of overstretching. Phase II is the mural thrombus formation which results from endothelium removal, and the exposure of deep vascular structures and induction of procoagulant factors. These thrombi are rich in cytokines and growth factors, including interleukin-1β, platelet-derived growth factor (PDGF), and transforming growth factor-β (TGF-β) [11]. Finally, phase III is marked by smooth muscle cell activation and synthesis of extracellular matrix. Phase III is considered to be crucial in the development of late lumen loss and can be divided into three different waves [2,12]. The first wave is characterized by replication of vascular smooth muscle cells (VSMCs) within the tunica media during the first 2 days after injury. Several lines of evidence suggest that basic fibroblast growth factor (bFGF) plays an important role in mediating this first wave of medial smooth muscle proliferation [13]. The second wave (day 2–14) of the response to injury involves the migration of VSMCs from the tunica media into the intima. PDGF appears to play an important role as a chemoattractant for VSMCs in this phase [14,15]. The third wave is characterized by intimal VSMC proliferation and accumulation of extracellular matrix, where both PDGF and bFGF continue to provide the stimulus for cell replication. In addition, TGF-β plays an important role in stimulating the VSMCs to produce excess extracellular matrix [16].

Where does IL-1β fit into these processes? Overwhelming evidence suggests that IL-1β is present and may play a role in different stages of experimental ‘restenosis’ in animal models, as well as in human atherosclerosis and restenosis. However, it is not yet clear where IL-1β is located in the cascade of events leading to restenosis after the injury. Chamberlain et al. [9] provide strong evidence that IL-1β along with Caspase-1 (also known as interleukin-1β converting enzyme, ICE) expression are induced in porcine coronary arteries as early as 1 h after balloon injury. Caspase-1 cleaves pro-IL-1β to generate mature IL-1β, and is necessary for IL-1β activation. IL-1β was found not only in inflammatory cells, but more importantly in endothelial cells and adventitial fibroblasts. What are the implications of these findings?

IL-1β is a pro-inflammatory cytokine with pleiotropic effects implicated in the development of atherosclerosis [17]. It is produced primarily in activated macrophages; however, a number of cell types including endothelial cells, VSMCs, and fibroblasts have been shown to produce IL-1β [17]. Several lines of evidence suggest that IL-1β actively participates in regulating vascular cell functions including stimulation of VSMC proliferation, stimulation of leucocyte adhesion to the endothelium, modulation of low density lipoprotein (LDL) metabolism, and induction of extracellular matrix protein, as well as matrix metalloprotease (MMP) production, increased vascular permeability, suppression of vascular contractility, and increased procoagulant activity. IL-1β is clearly up-regulated in coronary arteries of patients with ischemic heart disease [17]. Thus, IL-1β appears to be involved in the development of atherosclerosis as well as many aspects of the healing process following balloon injury of blood vessels.

Recently, Shimokawa et al. [18] found that IL-1β-containing beads placed in the adventitia of porcine coronary arteries induced intimal thickening similar to the effects of balloon injury. This effect is abolished by simultaneous treatment with neutralizing antibody to IL-1β, suggesting that IL-1β is directly involved in this process. This data, together with the Chamberlain et al. [9] finding that IL-1β in adventitial cells is up-regulated within 6 h after balloon injury, suggest the important role of adventitial IL-1β in the development of intimal hyperplasia. Clearly the implications of up-regulated IL-1β in adventitial cells are not limited to ‘neointima’ formation. In fact, ‘neoadventitia’ formation also appears to be a crucial mechanism for lumenal narrowing and vascular remodeling in porcine coronary arteries following balloon angioplasty [19,20]. Given the potential role of IL-1β in regulating extracellular matrix metabolism, it is tempting to speculate that IL-1β may mediate ‘neoadventitia’ formation as well.

It is clear, of course, that IL-1β is not the only factor which is induced very early after balloon injury, thus potentially triggering the cascade leading to restenosis. The fact that IL-1β as well as many other cytokines and growth factors have long been implicated in restenosis, but have never been put into a clear hierarchical order, illustrates the difficulty and complexity of restenosis in both animal models as well as patient material. Some of the methods (i.e. in situ RT-PCR) used by Chamberlain et al. [9] to address the role of IL-1β are rather unconventional, and have been considered super-sensitive and prone to artifact. However, the carefully conducted experiments presented here involve extensive positive and negative controls and deserve credit for being the first to show that IL-1β may indeed be a potential triggering factor in the porcine model of restenosis.

The question is now, is it possible to extrapolate this finding into clinical restenosis in patients? As described above, restenosis after PTCA in patients with preexisting atherosclerosis of the coronary artery is a very complex process. Most of our knowledge of restenosis has come from studies of balloon injuries in previously normal arteries in animal models. A number of drugs which show efficacy in animal models of restenosis do not work in patients [5], suggesting that these models mimic the human condition poorly, if at all. Nevertheless, animal models represent the only means of identifying the factors present in the early phase after the initial injury, which may trigger the cascade of wound healing, intimal hyperplasia, and/or arterial remodeling in the ‘restenosis’ process.

With these limitations in mind, the Chamberlain et al. [9] paper represents a step in the right direction in the systematic search of factors which could serve as a starting point to a successful therapeutic intervention for restenosis. If IL-1β is proven to be a critical factor, pharmacological approaches which inhibit the initial inflammatory reaction, potentially reducing the local burden of IL-1β and/or blocking of the IL-1β actions, will ultimately be effective in preventing the development of restenosis. In fact, several drugs which show a potential benefit for restenosis belong to this category. For example, the potent platelet glycoprotein IIb/IIIa receptor inhibitors such as abciximab, which reduces platelet aggregation dramatically, thereby reducing the release of platelet derived IL-1β, was found to reduce the incidence of restenosis by 26% at 6 months [21]. Complex problems often require complex solutions, and in this case a combination of powerful anti-inflammatory agents including IL-1β blockers might be necessary for the successful prevention and treatment of restenosis.


   Acknowledgements
 
The author wishes to thank Dr Deborah Hartman for the critical reading of the manuscript.


   References
Top
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