Cause of Blood Vessel Damage in People with Diabetes Discovered

Researchers have identified a key mechanism that appears to contribute to blood vessel damage in people with diabetes....

The researchers said studies in mice show that the damage appears to involve two enzymes, fatty acid synthase (FAS) and nitric oxide synthase (NOS) that interact in the cells that line blood vessel walls. First author Xiaochao Wei said, "We already knew that in diabetes there's a defect in the endothelial cells that line the blood vessels."

"People with diabetes also have depressed levels of fatty acid synthase. But this is the first time we've been able to link those observations together."

Wei studied mice that had been genetically engineered to make FAS in all of their tissues except the endothelial cells that line blood vessels. These so-called FASTie mice experienced problems in the vessels that were similar to those seen in animals with diabetes. "It turns out that there are strong parallels between the complete absence of FAS and the deficiencies in FAS induced by lack of insulin and by insulin resistance," said Clay F. Semenkovich, the Herbert S. Gasser Professor of Medicine, professor of cell biology and physiology and chief of the Division of Endocrinology, Metabolism and Lipid Research, Washington University in St. Louis, Missouri.

Comparing FASTie mice to normal animals, as well as to mice with diabetes, Wei and Semenkovich determined that mice without FAS, and with low levels of FAS, could not make the substance that anchors nitric oxide synthase to the endothelial cells in blood vessels. "We've known for many years that to have an effect, NOS has to be anchored to the wall of the vessel," Semenkovich said.

"Xiaochao discovered that fatty acid synthase preferentially makes a lipid that attaches to NOS, allowing it to hook to the cell membrane and to produce normal, healthy blood vessels." In the FASTie mice, blood vessels were leaky, and in cases when the vessel was injured, the mice were unable to generate new blood vessel growth.

The actual mechanism involved in binding NOS to the endothelial cells is called palmitoylation. Without FAS, the genetically engineered mice lose NOS palmitoylation and are unable to modify NOS so that it will interact with the endothelial cell membrane. That results in blood vessel problems.

It's a long way, however, from a mouse to a person, so the researchers next looked at human endothelial cells, and they found that a similar mechanism was at work.

"Our findings strongly suggest that if we can use a drug or another enzyme to promote fatty acid synthase activity, specifically in blood vessels, it might be helpful to patients with diabetes," Wei said.

Journal of Biological Chemistry. Jan. 2011