Two Enzymes Contribute to Blood Vessel Damage in Diabetes
Blood vessel problems are a common diabetic complication. Diabetes can lead to cardiovascular damage in a number of ways including an increased risk for atherosclerosis and tissue injury due to hypertension. Another key mechanism that contributes to blood vessel damage in diabetics has recently been identified by researchers at Washington University School of Medicine in St. Louis.
Blood Vessel Damage Can Lead to Amputations and Other Complications in Diabetics
The inner lining of the blood vessels is known as the endothelium. Damage to these cells can impair the regulation of blood flow. Fatty acid synthase (FAS) is an enzyme that is crucial to cellular structure. It also mediates the action of other biologically important molecules, including nitric oxide synthase (NOS) which plays a key role in dilating blood vessels.
The research team led by Xiaochao Wei PhD studied mice that had been genetically engineered to make fatty acid synthase (FAS) in all tissues except the endothelial cells that line the blood vessels. The mice, called FASTie, experienced problems in the vessels that were similar to those seen in animals with diabetes. For example, when blood vessels were damaged, the mice were unable to generate new growth. They were also more susceptible to infection.
Mice without FAS, or those with deficiencies induced by a lack of insulin and insulin resistance, could not make a lipid substance that anchors NOS to the endothelial cells in blood vessels. In order to generate nitric oxide, NOS has to be attached to cell membranes in the vessel wall in a mechanism called palmitoylation.
“We already knew that in diabetes there’s a defect in the endothelial cells (and that) people with diabetes also have depressed levels of fatty acid synthase,” said Dr. Wei. “But this is the first time we’ve been able to link those observations together.”
“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 says. “We also have been able to demonstrate that palmitoylation of nitric oxide synthase is impaired in diabetes, and if we can find a way to promote the palmitoylation of NOS, even independent of fatty acid synthase, it may be possible to treat some of the vascular complications of diabetes.”
Many of the 26 million Americans with diabetes face the prospect of amputations, heart attack, stroke, and vision loss due to damaged blood vessels.
Wei X, Schneider JG, Shenouda SM, Lee A, Towler DA, Chakravarthy MV, Vita JA, Semenkovich CF. De novo lipogenesis maintains vascular homeostasis through endothelial nitric-oxide synthase (eNOS) palmitoylation,Journal of Biological Chemistry, vol. 286(4), pp. 2933-2945. Jan. 28, 2011.