As the role of TGF-β and its signaling components in cardiovascular diseases is increasingly recognized, there is a growing interest in TGF-β as a therapeutic target. Several classes of inhibitors have been developed to antagonize the TGF-β pathway; many of which target ligand-receptor interactions. Examples of such inhibitors include anti-TGF-β antibodies, anti-receptor antibodies, TGF-β-trapping receptor ectodomain proteins, and small molecule inhibitors of TGF-β receptors. With the development of RNA interfering technology and nanotechnology, molecular agents targeting various Smad proteins could provide additional inhibitory strategies.
Targeting TGF-β in restenotic disease is not only supported by a vast body of experimental data but also by the fact that some of the TGF-β inhibitors have entered clinical trials for efficacy against cancers and fibrosis. However, we need to be very cautious in applying an anti-TGF-β strategy to restenotic patients as these patients may have underlying pathology such as atherosclerosis, diabetes or even occult malignancy. A major concern is the potential effect of an anti-TGF-β therapy on plaque instability and thrombosis. Once again, TGF-β’s role here is complicated. In humans, plasma TGF-β concentration has been found to be negatively correlated with atherosclerosis [87
]. Animal studies utilizing systemic suppression of TGF-β activity with neutralizing antibodies to TGF-β1, -β2 and –β3 or with a soluble TGF-β-receptor II protein have been found to accelerate the development of atherosclerosis and induce an unstable plaque phenotype [91
Undoubtedly, many challenges exist in the pathway of translating anti-TGF-β strategies to therapies for restenosis, and its primary limitation in success in clinical trials may be due to an incomplete understanding of TGF-β biology. Since TGF-β is a potent growth repressor for many types of cells, whether an anti-TGF-β therapy could lead to unwanted tumor growth is a sobering concern. Additionally, TGF-β function is context-dependent with differences in outcome related to the availability of its co-activators and co-repressors, ligand concentration, composition of its isoforms, cell type and concentration, and the various crosstalks associated with its primary signaling pathway Smad. In this regard, targeting downstream signaling proteins such as Smad, rather than ligand or receptor, might offer a selective attenuation of an unwanted TGF-β function and therefore a safer therapy to treat intimal hyperplasia. However, our understanding of the specificities of the Smads is very limited in vascular disease due to the lack of reliable approaches to selectively assess their function. This will present as a challenge when developing anti-Smad therapies.
It is important to note that a ‘TGF-β paradox’ exists. In cancer cells, TGF-β functions as a tumor suppressor initially and switches to a tumor promoter later [93
]. A similar paradox exists in TGF-β’s role in inflammation [94
]. Another important aspect is perhaps the temporal relationship between TGF-β up-regulation and other pathologic events. In restenosis, inflammation occurs initially followed by smooth muscle cell proliferation; TGF-β expression is followed by Smad expression. Therefore targeting TGF-β at specific time points during the disease process may be an option worth considering.
Vessel-specific drug delivery system such as catheter- or stent-based drug delivery devices may avoid unnecessary disruption of TGF-β signaling in other organ systems. As described in the various animal models employed by the authors cited, there are a number of techniques to deliver anti-TGF-β therapies with specific advantages. Intraluminal delivery is frequently employed and may be easier to translate to human use as in catheter- or stent-based delivery. This method targets primarily smooth muscle cells. The use of periadventitial application of therapies targets mainly periadventitial cells and may be used in conjunction with open surgery. Systemic therapies, while the easiest to use, are non-specific. However, this limitation could be overcome with the use of tissue-specific targeting through the so-called smart drug design, an approach requiring identification of molecular markers that are differentially up-regulated in restenotic vessels.
Therapeutic targeting of the TGF-β pathway in injured vessels is based on the rationale that TGF-β promotes intimal hyperplasia. However, some components of the TGF-β pathway may favor outward or adaptive remodeling, as shown by Kingston’s TGF-β3 study [10
] and by our own Smad3 study [70
]. Additionally, the TGF-β/Smad signal may lead to different biological outcomes in different cell types as shown by Feinberg’s MCP-1 study in macrophages [86
] and ours in SMCs [60
]. Therefore, a better understanding of various TGF-β ligands and their signaling mechanisms following vascular injury is crucial. Finally, targeting TGF-β might cause chronic inflammatory and autoimmune reactions, which could potentially worsen atherosclerosis or diabetes, conditions that are frequently associated with restenotic patients.
As we progress toward individualized medicine, studies designed to delineate the multifunctional effects and mechanisms of TGF-β in different restenotic lesions (for example: coronary versus peripheral, carotid versus femoral, and arterial versus venous) are essential. Equally important is the evaluation of TGF-β function in patients associated with different risk factors such as diabetes, smoking, and aging to determine when and how anti-TGF-β therapy might be feasible. For example, TGF-β levels have been found to be elevated in patients with diabetes mellitus type I [95
] and have been correlated with an increased risk of developing diabetes mellitus type II [96
]. Moreover, it has been implicated in the pathogenesis of diabetes nephropathy [97
], and cigarette smoke may produce an additive effect in its development [99
]. On the contrary, TGF-β has been associated with longevity [100
] and healthy individuals compared with Alzheimer’s patients [101
]. The idea is that restenotic lesions developed in different vascular beds or in different individual patients may have different underlying pathophysiology. Therefore, we need to develop diagnostic tools that allow the analysis of TGF-β signaling and measurable downstream effectors of TGF-β’s functions in individual patients, which will ultimately enable us to identify and select patients who would possibly derive the most benefit from an anti-TGF-β therapy.