Researchers Say Good Cholesterol Can Turn Bad

November 10, 1997

ORLANDO, Nov. 10 -- Long considered the "good" cholesterol, HDL under some circumstances can be made to act like its evil twin LDL and promote atherosclerosis, according to researchers who spoke today at the American Heart Association Scientific Sessions.

The scientists reported that they have new evidence of how HDL -- high-density lipoprotein cholesterol -- can turn bad. This finding may point to new ways to battle atherosclerosis, which occurs when cholesterol and other fats are deposited in the artery wall in waxy deposits called plaque. Atherosclerosis causes the obstructions in the blood vessels that trigger heart attack and strokes

The new studies suggest that HDL can, under some circumstances, actually help trigger an inflammatory reaction in the blood vessels and accelerate atherosclerosis.

The studies add further weight to the new theory that atherosclerosis is an inflammatory disease, rather than a degenerative disease that is an inevitable consequence of aging. And the studies suggest that medicines that treat inflammation, such as aspirin, might be useful in preventing or controlling atherosclerosis, report Diana Shih, Ph.D., and Alan Fogelman, M.D., at the University of California, Los Angeles.

Scientists believe that HDL defends the body against atherosclerosis by removing excess cholesterol and transporting it to the liver. New studies suggest that HDL also has antioxidant properties much like vitamins E or C. Antioxidants disable oxygen-free radicals, unstable molecules that double-up with LDL, or low-density lipoprotein, forming oxidized LDL.

In a report today, Shih and colleagues describe results of experiments on a knock-out mouse model. A knock-out mouse has a particular gene removed so that researchers can identify what action the gene has by looking at what happens when the gene is absent.

The California team developed a knock-out mouse for a gene for paraoxonase, an enzyme that has been identified as one of the major antioxidant defenses in HDL. Without the paraoxonase, the mouse's HDL could not prevent LDL oxidation, and in fact, HDL itself turned on the immune system, causing more white blood cells to collect in the blood vessel, says Shih. The model blood vessel developed by the California team has proved to be a useful way to detect if HDL was converted from an anti-inflammatory to a pro-inflammatory agent.

The process of plaque obstructions that impair blood flow begins when oxidized LDL is trapped in the blood vessels and some of the phospholipids (emulsifiers that help it mix with blood) in LDL become oxidized. This sets off a "call to arms," to activate the immune system to produce white blood cells. As a result cholesterol, calcium and other cellular components collect in the inner layers of the vessel wall and narrow the channel through which blood flows in the artery.

Heart attacks and strokes are caused when plaque obstructions rupture. Upon coming in contact with the plaque contents, the flowing blood clots and causes a complete obstruction of blood flow. As the heart muscle continues to contract without fresh blood, cells die and cause a heart attack.

HDL normally contains antioxidant enzymes such as paraoxonase that can destroy the oxidized lipids in LDL that are the "call to arms" and hence HDL prevents or calms the inflammatory reaction and thereby prevents heart attacks and strokes.

During an acute phase reaction (a heightening of the immune system that evolved to protect humans from infection in the eons before antibiotics) such as that which occurs after surgery, HDL loses its paraoxonase activity and is converted from an anti-inflammatory molecule to one which actually stimulates the immune response and may promote plaque rupture.

Now that researchers better understand HDL's action in the blood vessels, they can begin to search for new therapies that will enhance the paraoxonase activity or at least prevent it from being lost during periods of heightened immune responses.

Thus, they say atherosclerosis may in part be thwarted by anti-inflammatory medicines such as aspirin.

With continued research new treatments may be found that can enhance the HDL's enzyme activity giving it more muscle against atherosclerosis, says Folgelman. Having high blood levels of HDL is desirable because in general the higher the level of HDL, the higher the level of paraoxonase. In the future, there may be ways of enriching HDL in paraoxonase and preventing its loss during periods of heightened immune response as occurs after surgery and with certain kinds of infections, and thus keep the "good" HDL from going "bad."

Co-authors are Mohamad Navab, Ph.D., and Aldons J. Lusis, Ph.D.,

American Heart Association

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