The study, published online in Cardiovascular Research, reports that one of the scorpion’s toxins, margatoxin, is at least 100 times more potent at preventing neointimal hyperplasia – the most comon cause of bypass graft failure – than any other known compound.
Neointimal hyperplasia is the blood vessel’s response to injury. It triggers the growth of new cells, causing chronic obstruction on the inside of the vessel.
When a vein is grafted onto the heart during a bypass procedure, the injury response kicks in as the vein tries to adapt to the new environment and different circulatory pressures. Whilst the growth of new cells helps to strengthen the vein, the internal cell growth restricts blood flow and ultimately causes the graft to fail.
The potency of the margatoxin in suppressing the injury response mechanism took the team by surprise, says lead author Professor Beech from the University’s Faculty of Biological Sciences. “It’s staggeringly potent. We’re talking about needing very few molecules in order to obtain an effect.”
The toxin works by inhibiting the activity of a specific potassium ion channel – a pore in the cell membrane that opens and closes in response to electrical signals and indirectly enhances delivery of a intracellular messenger, the calcium ion.
“We knew from experimental research in immunology that the ion channel Kv1.3 is involved in activating immune system responses and that it’s linked with chronic inflammation problems in the immune system, such as those you see with multiple sclerosis,” says Professor Beech. “Since our own studies had identified Kv1.3’s presence in injured blood vessels, which are also often complicated by chronic inflammation, we wanted to see if the same immune system blockers would inhibit neointimal hyperplasia.”
“There were a number of good blockers of this ion channel available to screen. Several compounds are developed from plants, and one comes from scorpion venom,” he says, “but margatoxin was the most potent of all these compounds by a significant margin.”
Professor Beech says margatoxin would probably be unsuitable as a drug that could be swallowed, inhaled or injected, but it could potentially be taken forward as a spray-on treatment to the vein itself once it’s been removed and is waiting to be grafted onto the heart.
The research was funded by the British Heart Foundation, the Wellcome Trust and the Medical Research Council.
Professor David Beech is available for interview
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Notes to editors
- Potent suppression of vascular smooth muscle cell migration and human neointimal hyperplasia by KV1.3 channel blockers
Alex Cheong; Jing Li; Piruthivi Sukumar; Bhaskar Kumar; Fanning Zeng; Kirsten Riches; Christopher Munsch; Ian C. Wood; Karen E. Porter; David J. Beech
Cardiovascular Research 2010; doi: 10.1093/cvr/cvq305. A copy of the paper is available here: http://bit.ly/agLIFv )
- David Beech is Professor of Molecular and Cellular Physiology in the Institute of Membrane and Systems Biology http://www.fbs.leeds.ac.uk/staff/profile.php?tag=Beech
- Despite the rise in less invasive procedures such as stents to treat coronary heart disease, some 25,000 coronary artery bypass grafts (CABG) are carried out each year in the UK (source: British Heart Foundation). Successful CABGs typically last around 10-15 years.
- Centruroides margaritatus, also known as the Central American bark scorpion, is native to Central and South America. Typical examples are 5-8 cm long, including the tail. Is not deadly to humans but has a painful sting that causes swelling and tingling.
- The Faculty of Biological Sciences at the University of Leeds is one of the largest in the UK, with over 150 academic staff and over 400 postdoctoral fellows and postgraduate students. The Faculty is ranked 4th in the UK (Nature Journal, 457 (2009) doi :10.1038/457013a) based on results of the 2008 Research Assessment Exercise (RAE). The RAE feedback noted that “virtually all outputs were assessed as being recognized internationally, with many (60%) being internationally excellent or world-leading” in quality. The Faculty’s research grant portfolio totals some £60M and funders include charities, research councils, the European Union and industry. www.fbs.leeds.ac.uk
- The 2008 Research Assessment Exercise showed the University of Leeds to be the UK’s eighth biggest research powerhouse. The University is one of the largest higher education institutions in the UK and a member of the Russell Group of research-intensive universities. The University’s vision is to secure a place among the world’s top 50 by 2015. www.leeds.ac.uk
- British Heart Foundation (BHF)
The British Heart Foundation is the nation’s heart charity, dedicated to saving lives through pioneering research, patient care, campaigning for change and by providing vital information. But we urgently need help. We rely on donations of time and money to continue our life-saving work. Because together we can beat heart disease. For more information visit www.bhf.org.uk/pressoffice
- The Wellcome Trust
The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust’s breadth of support includes public engagement, education and the application of research to improve health. It is independent of both political and commercial interests. www.wellcome.ac.uk
- Medical Research Council (MRC)
For almost 100 years the Medical Research Council has improved the health of people in the UK and around the world by supporting the highest quality science. The MRC invests in world-class scientists. It has produced 29 Nobel Prize winners and sustains a flourishing environment for internationally recognised research. The MRC focuses on making an impact and provides the financial muscle and scientific expertise behind medical breakthroughs, including the first antibiotic penicillin, the structure of DNA and the lethal link between smoking and cancer. Today MRC funded scientists tackle research into the major health challenges of the 21st century. www.mrc.ac.uk