Sci. Aging Knowl. Environ., 21 January 2004
New artery-cleaning agents might provide statin backup
The number of tools to fight heart disease could be mushrooming. Two fungal compounds slow down artery-clogging lipid buildup in mice, a new study finds, and they work through a different pathway than current treatments do. The drugs might reinforce existing therapy or take over when other medicines fail.
Lipids in the blood--including LDL ("bad") cholesterol and triglycerides--can form gunky deposits. These so-called plaques narrow blood vessels, causing atherosclerosis, which can lead to heart attack or stroke (see "Greasing Aging's Downward Slide"). Preventive treatments block lipid production. Statins, the current drugs of choice, thwart an enzyme called HMG-CoA reductase, narrowing the main gateway to LDL accumulation. Statins reduce the risk of heart attack and stroke, but only by about one-third, and they don't work in all patients. So researchers are seeking other therapies.
Drugs that hamper the enzyme acyl-CoA:cholesterol acyltransferase (ACAT) could starve plaques by slowing production of cholesterol esters, the form of cholesterol that's packaged in LDL. Although ACAT inhibitors slow plaque formation in animals, synthetic versions produce troublesome side effects such as diarrhea; completely inactivating one form of the enzyme, ACAT-1, kills immune cells called macrophages. So focus has shifted to treatments that partially block ACAT-1 and also inhibit another form of the enzyme, ACAT-2.
While seeking new antiatherosclerosis compounds, Hiroshi Tomoda, a biochemist at Kitasato University in Tokyo, and colleagues found two fungal products, called beauveriolides I and III, that decrease lipid buildup in macrophages--a hallmark of atherosclerosis. They wondered whether the compounds foil ACATs. The researchers treated cultured mouse and human cells with beauveriolides; cholesterol ester quantities plummeted. Biochemical tests confirmed that the chemicals block both ACAT-1 and -2; furthermore, they're more potent against ACAT-2. Next, the scientists tested the agents on atherosclerosis-prone mice. Animals that ate beauveriolide III had smaller plaques in the aorta and heart than did untreated controls. The rodents showed no undesirable effects during the 2-month study.
Despite these observations, some scientists are skeptical because previous promising results in animals haven't panned out in humans. "I've heard this [optimism] before with ACAT inhibitors," says Prediman Shah, a cardiologist at Cedars-Sinai Medical Center in Los Angeles, California.
Biochemist Lawrence Rudel of Wake Forest University Baptist Medical Center in Winston-Salem, North Carolina, is more optimistic. "The pharmaceutical industry [has been] looking at ACAT inhibitors for some 20 years, and they never came up with much," he says. "But these Japanese guys are pulling these compounds out of natural sources. The chemical nature of the beauveriolides is the key. It seems to be different." Beauveriolides contain an unusual type of building block called D-amino acid that makes them particularly stable, Rudel says. So they stay whole and able to do their jobs.
Tomoda says that he hopes the beauveriolides will work for people in whom the statins do not, or in tandem with statins. Scientists have already shown that a synthetic ACAT inhibitor called avasimibe enhances one statin's effects. With their stability and lack of apparent side effects, the beauveriolides might perform even better and bring ACAT inhibitors out of the woods.
January 21, 2004
Science of Aging Knowledge Environment. ISSN 1539-6150