“This is a previously unexplored track that can explain how high blood sugar levels damage the blood vessels”, says Maria Gomez, scientist at LUDC and the responsible author of the article, which is published online today in the journal Arteriosclerosis, Thrombosis and Vascular Biology.
At the end of the chain is the protein osteopontin. “Osteopontin is the black sheep of vascular biology. We know that elevated levels of this protein set off a cascade of inflammatory events that injures the blood vessel walls”, says Maria Gomez.
It is already known that diabetics have elevated levels of osteopontin in their blood and that there is a strong connection with diabetes complications. Inflammation is a basic mechanism underlying atherosclerotic plaque formation, which causes cardiac infarction and stroke. These diseases are the cause of death of 70 to 80 percent of all diabetics and approximately half of Swedish non-diabetics.
The focus of Maria Gomez’s research group is on how cells in the vascular walls react to changes in the sugar concentration and how this is translated to the changes in gene expression that will subsequently lead to vessel damage.
In previous experiments, performed on mouse vessels, the group has shown that another protein, NFAT, is activated by high blood sugar. “The main questions for this study was whether this was also true in living animals and if the increased NFAT activity is responsible for the increase of osteopontin to detrimental levels”, says Lisa Nilsson-Berglund, the main author of the article.
To be able to investigate this connection, the scientists used mice that have been genetically modified so that their tissues emit light when NFAT is activated. The method is based on the same enzymes used by many luminescent animals, such as fireflies and jellyfish.
When diabetes was induced in the genetically modified mice, causing the blood sugar levels to rise, the vessels started to glow. “We investigated different types of vessels, e.g. aorta and cerebral arteries”, says Lisa Nilsson-Berglund and adds that they could confirm that the mechanism was the same in living animals as in the test tubes.
Several steps in the process had now been established. The NFAT-protein functions as a sugar sensor that is activated when the concentration of sugar in the blood is increased. The question of whether there was a causal connection between NFAT and osteopontin remained to be answered.
Through a series of experiments using, among other things, knock-out mice that do not produce NFAT, the research group could show that the protein really plays a key role in determining the osteopontin levels in blood vessels. “The knock-out mice had normal osteopontin levels in spite of having high blood sugar”, says Maria Gomez.
New mechanism underlying cardiovascular disease
Hyperglycemia starts a complex chain of events that damages blood vessels and cause cardiovascular disease. Scientists at Lund University Diabetes Centre (LUDC) have now been able to demonstrate why this happens, as well as how the destructive chain can be broken. This discovery represents a crucial step towards an efficient treatment of the vascular injuries that will be the cause of death for most diabetes patients.