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.
Pigs ‘edited’ with a warthog gene to resist African swine fever could help spawn GM animal farms in the UK
Mouse House to make naturalist biopic, six years after box-office failure of Creation, starring Paul Bettany
International team spends 10 years making inroads into treatment of bacterium which kills up to half of those it infects
You may not know it, but you probably have some Neanderthal in you. For people around the world, except sub-Saharan Africans, about 1 to 3 percent of their DNA comes from Neanderthals, our close cousins who disappeared roughly 39,000 years ago.
Research at Yale plotted what happened in the brains of two scientists as they held a conversation
From medicines to jet fuel, we have so many reasons to celebrate the microbes we live with every day
Genome sequencing indicates Kennewick Man is Native American, reopening the bitter battle over whether he should be reburied or studied
In the article on the discovery of dinosaurs (They’re back, Review, 6 June) you state: “In Sussex, a local doctor uncovered fragmentary remains of what appeared to be two more species of colossal extinct land reptiles.” You grossly underplay the contribution of Lewes-born Gideon Mantell, geologist and palaeontologist, author and diarist, friend to princes and international scholars as well as local doctor. Mantell not only discovered (aided by his wife) the first remains of the iguanodon in 1824 but named it – as it resembled the tooth of an iguana. This was the first known land dinosaur, Mary Anning having identified the first sea-living dinosaur.Mantell went on to put together more pieces of the jigsaw with extra fossil discoveries. In contrast to Richard Owen, whose models form the basis for the Crystal Palace dinosaurs, Mantell stated correctly that iguanodon would have walked on their back legs, using their forearms to fight or gather food. He did, however, attribute the thumb spike to a nose horn though later corrected this assumption. The Natural History Museum has a display on Gideon and his wife Mary’s contribution as well as the large “Mantell-piece” of Iguanodon fossils that he had on show in his museum in Brighton. He sold it, along with many more priceless items, to the British Museum in 1838. Gideon Mantell’s reputation deserves better than your throwaway remark. Debby MatthewsLewes, East Sussex Continue reading...
Unique triangular hairs help keep Saharan silver ants cool at 70°C by manipulating the physics of light
Most animals wouldn't confront a fearsome predator like a lion. But through sophisticated group work, hyenas launch successful raids