Pharmacological activation of transforming growth factor-beta1 (TGF-beta1) may be of benefit as a stroke prevention strategy

About 700,000 Americans suffer a new or recurrent stroke each year usually due to atherosclerosis in the carotid/vertebral arteries. Recovery from stroke is unpredictable and rarely complete and consequently 15-30% of ischemic stroke victims are permanently disabled and 20% require prolonged institutional care. As a result, stroke is the most common cause of long-term serious disability in the and represents a massive economic burden.

Strokes usually occur when atherosclerotic plaques rupture and thrombi which form as a result occlude the cerebral vasculature. Thrombolytic agents which break down these blood clots are used as an acute treatment of stroke however the window of opportunity for such intervention is very narrow and much attention is therefore being focussed on the prevention of stroke occurrence (or reoccurrence) in at risk individuals. Since atherosclerosis is central to the etiology of stroke targeting this process is attractive.

Atherosclerosis is common to many cardiovascular diseases including stroke, myocardial infarction and peripheral arterial disease (editorial note: The circulation of this editorial coincides with the publication of a key pharmaceutical report on the unmet needs of this condition - click here for more). Atherosclerosis affects nearly 174 million individuals in the major pharmaceutical markets in 2000, and consequently during 2000-2010, total sales of anti-atherosclerosis therapies will grow robustly, to in excess of US$13.7billion by 2008.

Atherosclerotic plaques consist of accumulated intracellular and extracellular lipids, ooth muscle cells, connective tissue, and glycosaminoglycans. The earliest detectable lesion of atherosclerosis is a fatty streak consisting of lipid-laden foam cells. As the atherosclerotic process progresses plaa LDL cholesterol penetrates the vascular wall, leading to lipid accumulation in ooth muscle cells and in foam cells. Consequently statins, inhibitors of HMG-CoA reductase, a rate limiting step in the synthesis of endogenous cholesterol, represent the primary pharmacological approach to the treatment of atherosclerosis (for a listing of available pharmaceutical reports evaluating dislipidemia and the statins click here). In recent studies two statins, atorvastatin have been found to reduce the incidence of fatal and non-fatal stroke by 25-35%. These findings have been hotly debated since LDL cholesterol elevation does not appear to be a strong risk factor for stroke.

Inflammation is now accepted as a central feature of atherosclerosis. Foam cells are macrophages that have migrated as monocytes from the circulation into the subendothelial layer of the intima. In addition to the presence of foam cells, T cells feature prominently in plaques. Macrophages, foam cells and T cells all promote local inflammation and neointimal growth through the expression of cytokines and growth factors, especially in the context of hypercholesterolemia. This active inflammatory process promotes the formation of unstable "vulnerable" atherosclerotic plaque.

In addition to inflammatory cells, vulnerable plaques are characterized by the relative absence of ooth muscle cells, a large lipid pool and a thin fibrous cap that ruptures easily under the influence of mediators secreted by the inflammatory cells. Plaque rupture activates the thrombotic process that precedes stroke. Stable plaques, in contrast, have few inflammatory cells, dense extracellular matrix, a aller lipid pool, and a thick fibrous cap. The development of plaque stabilizing therapeutic agents is becoming an increasingly sought after objective. Of considerable interest the statins may exert their effect in part through the stabilization of plaques thereby explaining their efficacy in preventing stroke.

A number of inflammatory mediators have been implicated in atherosclerosis. One anti-inflammatory mediator is transforming growth factor-beta (TGF-beta). In addition to limiting inflammation this growth factor may control vascular ooth muscle proliferation and extracellular matrix deposition. TGF-beta is present in human atherosclerotic plaques and is involved in the balance between inflammation and fibrosis within the plaque. Animal studies have shown that blocking TGF-beta signalling accelerates atherosclerosis by decreasing vascular collagen content and increasing inflammation.

Most recently Cipollone et al have demonstrated that heightened levels of TGF-beta1 may stabilize plaques in patients at risk of stroke or in those that have already suffered a stroke. In their article due to be published in the October edition of the journal Stroke, this group determined TGF-beta levels in surgical specimens taken during endarterectomy from symptomatic patients (ie those that had recently suffered stroke or transient ischemic attacks) or asymptomatic patients (those in which carotid artery stenoses were identified following investigation for coronary disease or PAD). Histological evaluation demonstrated that symptomatic patients, despite exhibiting a similar level of stenosis, had plaques judged to be considerably less stable both in terms of the degree of plaque ulceration and the presence of T cells and macrophages. Unstable plaques were found to contain almost three-times less TGF-beta1 than stable plaques a finding mirrored by the dramatic reduction in procollagen and collagen content in unstable plaques.

These data, when taken along side animal studies demonstrating that blocking TGF-beta1 can accelerate the atherosclerotic process, suggest that therapeutic agents able to enhance the activity of TGF-beta1 may be of use in the stabilization of plaques and the prevention of stroke.

Source: Increased Expression of Transforming Growth Factor-{beta}1 as a Stabilizing Factor in Human Atherosclerotic Plaques. Stroke. October, 2004

This article is highlighted in the August 26th edition of DailyUpdates - Cardiovascular disease, LeadDiscovery’s unique bulletin of breaking journal articles and press releases for the drug discovery community. To access the article and to view today’s bulletin click here