Researchers at Case Western Reserve University School of Medicine have identified a genetic factor that prevents blockages from forming in blood vessels, a discovery that could lead to new therapies for cardiovascular diseases.
The findings are described in the Nov. 19 issue of the Journal of Clinical Investigation.
Researchers led by Mukesh K. Jain, MD, FAHA, professor of medicine, Ellery Sedgwick Jr. Chair and director of Case Cardiovascular Research Institute at Case Western Reserve School of Medicine, found that a shortage of the genetic factor KLF4, which regulates endothelial cells lining the interior of blood vessels, makes the lining more prone to the buildup of harmful plaque and fat deposits. In addition they showed that the deficiency of KLF4 also made the blood vessel more susceptible to clot formation. The plaque buildup (called atherosclerosis) narrows vessels and provides the foundation for clot formation (called thrombosis) that leads to heart attack and stroke.
Conversely, sufficient levels of KLF4, protect the inner lining of blood vessels, from toxins and other harmful agents that trigger the buildup of plaque and clot formation.
"This research answers a fundamental question in blood vessel health, identifying KLF4 as a master regulator of the most cardinal functions of endothelial cells," says Jain, who is also chief research officer of Harrington Heart & Vascular Institute at University Hospitals Case Medical Center.
"The fact that the level of these genetic factors can be altered in human disease suggests that targeting them may be a viable therapeutic strategy," Jain says.
The researchers are now developing tools to identify small molecules that increase KLF4 levels. Long-term, the goal is to identify a new class of molecules to develop a drug that works with those already used to treat heart disease. Another possibility is to modify existing drugs that can boost KLFs levels.
"It is possible," Jain says, "that chemical modification of the current statins will create super-statins that are more potent at inducing KLF levels, providing additional benefit."
Studies have shown that the earliest lesions of atherosclerosis typically begin at points where blood vessels branch out to different parts of the body, such as the brain, heart and legs.
Researchers hypothesized that mechanical forces may irritate the lining at these intersections, making them more prone to atherosclerosis than straighter lengths of the vessel system. In addition, toxins and harmful cytokines – cell secretions that can trigger inflammation - can further injure the endothelium and speed the development of disease.
However, the molecular reasons for this have remained elusive until now.
When healthy, endothelium helps preserve normal, unobstructed blood flow. Tightly bonded endothelial cells prevent blood vessels from leaking and clotting, and ward off toxins and harmful cytokines.
"These anti-adhesive, anti-clotting, and anti-permeable properties of the endothelial surface are vitally important as they enable the smooth transport of blood, oxygen and nutrients to cells throughout the body," says Jain.
In prior in vitro studies, Jain's research group identified KLF4 and another genetic factor, KLF2, as agents that promote healthy functioning of the endothelium. Their work also indicated that increased levels of KLF factors allowed endothelial cells to block injury induced by toxins and cytokines.
In the new study, researchers used mouse models to more precisely determine the role KLF4 plays in preventing atherosclerosis and thrombosis, a leading cause of death and disability worldwide.
Over several years, the researchers generated mice that had either high or low levels of KLF4 in the endothelium. The animals were fed a high-fat diet for five to six months to mimic the unhealthy eating habits seen in much of the industrialized world.
The researchers found that, despite the fatty diet, mice with high levels of endothelial KLF4 were protected from developing atherosclerosis and thrombosis. Those lacking KLF4 had higher levels of plaque buildup and disease and were less able to prevent harmful cells from damaging blood vessels.
Case Western Reserve University: http://www.case.edu
This press release was posted to serve as a topic for discussion. Please comment below. We try our best to only post press releases that are associated with peer reviewed scientific literature. Critical discussions of the research are appreciated. If you need help finding a link to the original article, please contact us on twitter or via e-mail.
Free-living songbirds show increased stress hormone levels when nesting under white street lights. But different light spectra may have different physiological effects as this study finds, suggesting that using street lights with specific colour spectra may mitigate effects of light pollution on wildlife
Scientists identify the condition aphantasia, in which people cannot create images in their head
The dust in our homes contains an average of 9,000 different types of fungi and bacteria, a study suggests.
A mosquito can bear up to 23 times its total body weight on each leg, which is crucial for landing on water – the insect's secret is way it stands
Tropical species with smaller geographical ranges are more likely to die out in a warming climate than those that can adapt by ‘invading’ new regions
Most people think of bacteria as germs, signs of filth, or unwanted bringers of disease. Slowly, that view …
The gloomy octopuses crowded at Jervis Bay, Australia, appear to spit and throw debris such as shell at each other in what could be an intentional use of weapons
Therapies based on hormones that make us more trusting enhance our natural placebo effect – a finding that could alter the way clinical trials are conducted
The blind, hairless babies born recently at Washington D.C.'s National Zoo are completely dependent on their mothers—who can sometimes accidentally crush them.
The poop-hoarding insects have an amazingly advanced internal GPS that allows them to navigate by day or night.