Researchers Discover Root Cause of Blood Vessel Damage in Diabetes

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This certainly implicates toxic exposure. Read also Epidemic of Multiple

Chemical Sensitivity, A Disease Caused by Toxic Chemical Exposure.

_http://www.ehw.org/documents/MCS-press.pdf_ (http

://www.ehw.org/documents/MCS-press.pdf)

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Researchers Discover Root Cause of Blood Vessel Damage in Diabetes

_http://www.newswise.com/articles/researchers-discover-root-cause-of-blood-v

essel-damage-in-diabetes_

(http://www.newswise.com/articles/researchers-discover-root-cause-of-blood-vesse\

l-damage-in-diabetes)

Released: 1/28/2011 3:30 PM EST

Source: Washington University in St. Louis

A key mechanism that appears to contribute to blood vessel damage in

people with diabetes has been identified by researchers at Washington

University

School of Medicine in St. Louis.

Blood vessel problems are a common diabetes complication. Many of the

nearly 26 million Americans with the disease face the prospect of amputations,

heart attack, stroke and vision loss because of damaged vessels.

Reporting in the Journal of Biological Chemistry, the Washington

University researchers say 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.

**We already knew that in diabetes there’s a defect in the endothelial

cells that line the blood vessels,†says first author Xiaochao Wei, PhD. “

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 is a postdoctoral research scholar in the lab of Clay F. Semenkovich,

MD, the Herbert S. Gasser Professor of Medicine, professor of cell biology

and physiology and chief of the Division of Endocrinology, Metabolism and

Lipid Research.

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,** Semenkovich says.

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 says. **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.

**In animals that don’t have fatty acid synthase and normal nitric oxide

synthase in endothelial cells, we saw a lot of leaky blood vessels,**

Semenkovich explains. **The mice also were more susceptible to the consequences

of infection, and they couldn’t repair damage that occurred — problems that

also tend to be common in people with diabetes.**

In one set of experiments, the researchers interrupted blood flow in the

leg of a normal mouse and in a FASTie mouse.

**The control animals regained blood vessel formation promptly,**

Semenkovich says, **but that did not happen in the animals that were modified

to be

missing fatty acid synthase.**

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 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.**

And it shouldn’t matter whether a person has type 1 diabetes and can’t

manufacture insulin or the more common type 2 diabetes, in which a person

becomes resistant to insulin.

**That’s one of the key findings,** Semenkovich says. **It won’t matter

whether it’s an absence of insulin or resistance to insulin: both are

associated with defects in FAS.**

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.

This work was supported by grants from the National Institute of Diabetes,

Digestive and Kidney Diseases and the National Heart, Lung, and Blood

Institute of the National Institutes of Health and by awards from the American

Heart Association and the American Diabetes Association.

Washington University School of Medicine’s 2,100 employed and volunteer

faculty physicians also are the medical staff of -Jewish and St. Louis

Children's hospitals. The School of Medicine is one of the leading medical

research, teaching and patient care institutions in the nation, currently

ranked fourth in the nation by U.S. News & World Report. Through its

affiliations with -Jewish and St. Louis Children's hospitals, the School

of

Medicine is linked to BJC HealthCare.

_http://www.newswise.com/articles/researchers-discover-root-cause-of-blood-v

essel-damage-in-diabetes_

(http://www.newswise.com/articles/researchers-discover-root-cause-of-blood-vesse\

l-damage-in-diabetes)

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