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Promising strategy to make atherosclerotic plaques more stable
A study carried out by EVGN scientists from Bristol and Glasgow, with colleagues from the Baylor College of Medicine (Houston, Texas)*, indicates a potential new therapeutic approach for myocardial infarction. The scientists showed that the stability of atherosclerotic plaques - lipid-rich deposits that clog up the lumen of arteries - is markedly augmented when an enzymatic inhibitor (called TIMP-2) is present for long periods. The discovery was published in the May 15th issue of Circulation and has stimulated great interest in the scientific community because of its potential clinical applications.
Atherosclerotic plaques are brittle layers that easily tear apart, producing fragments which can arrest blood flow and cause myocardial infarction. Recent evidence suggests that endogenous enzymes called metalloproteinases (MMPs) play a pivotal role in this process: their presence within plaques is associated with destabilization and eventual rupture. For this reason EVGN scientists from Bristol and Glasgow, in collaboration with colleagues from the USA, investigated whether boosting the level of endogenous inhibitors of MMPs could modify the plaques’ behaviour. “We focussed on two TIMPs (proteins known to inhibit MMPs) because they have been detected in atherosclerotic plaques and are synthesized by smooth muscle cells (SMCs) and macrophages present within the plaques” explains Sarah J. George, senior author of the study from the Department of Clinical Medicine at the Bristol Heart Institute at the University of Bristol. “The idea was to experimentally increase the TIMP levels to see how this would affect the plaques”.
The researchers exploited gene transfer techniques in an atherosclerotic mouse model to augment circulating TIMP-1 and 2. “TIMP-2 gave the best results” observes George. “The first striking outcome of its overexpression was a reduction of the plaque’s protruding surface (cross-sectional area) within the vessel, and a smaller number of buried fibrous caps”. In general, the atherosclerotic lesions were more stable and no further size increase could be detected even 11 weeks after gene transfer. “Also”, points out George, “when circulating TIMP-2 was increased for some time, we observed significant changes in the cellular content of plaques, with less macrophages, more SMCs, and reduced apoptosis (programmed cell death)”. The change in apoptosis is important because when apoptotic events are attenuated, lipid accumulation occurs at slower rates and this decreases the build-up of cellular debris which would otherwise act as a pro-inflammatory factor. “This is like a domino effect” says Sarah George “whose ultimate consequence is more plaque stability”.
Further investigations will determine whether TIMP-2 could be a novel therapeutic agent, able to promote the stability of atherosclerotic lesions in human patients.
The full paper is available at: “Suppression of Atherosclerotic Plaque Progression and instability by Tissue Inhibitor of Metalloproteinase-2. Involvement of Macrophage migration and Apoptosis”, Circulation 2006; 113: 2435-44. Jason L. Johnson PhD*, Andrew H. Baker PhD, Kazuhiro Oka PhD, Lawrence Chan MBBS, DSc, Andrew C. Newby PhD, Christopher L. Jackson PhD, and Sarah J. George PhD.
* The following Institutions took part in the research: Bristol Heart Institute, University of Bristol (Bristol, England); the British Heart Foundation Glasgow Cardiovascular Research Centre, Division of Cardiovascular and Medical Sciences, University of Glasgow (Glasgow, Scotland); the Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine (Houston, Texas, USA).