August 28, 2000
Volume 53, No. 1
Josiah Wilcox cuts through the fat of atherosclerosis
By Poul Olson
It happens to all of us throughout our lives. Fat deposits called plaques build inside arteries, reach a critical mass and burst.
For most people, the event occurs unnoticed. But for others, dislodged plaques produce clots, blocking blood flow through the heart or brain and causing a potentially life-threatening heart attack or stroke.
Some 500,000 Americans die each year from heart disease caused by atherosclerosis, making it the nation's leading cause of death. Millions more must undergo surgery to reopen blocked arteries. A high-fat diet is one of the greatest factors contributing to atherosclerosis, but scientists have only a limited understanding of the biological processes involved in development of the disease.
Nearing an end is a series of studies led by Yerkes affiliate scientist Josiah Wilcox. For nearly a decade, a group of 24 male cynomolgus monkeys have been fed a daily diet consisting of 40 percent saturated fat-the equivalent of eating nothing but Big Macs every day.
The monkeys provide an ideal model for studying atherosclerosis because they metabolize cholesterol in much the same way as humans. Although the Yerkes cynos have all been fed the same diet, their cholesterol levels range from 150 to 600. Cholesterol levels below 150 are considered normal, while more than 300 can be life-threatening.
Serum cholesterol typically provides the best measure of one's risk for developing atherosclerosis. With a sustained elevation, plaques resembling small tumors develop on the walls of arteries.
Medications called "statins" are designed to lower cholesterol levels by inhibiting the body's synthesis of fat. Evi-dence suggests that these drugs, when taken in combination with a low-fat diet, also improve the functioning of arteries affected by atherosclerosis.
Wilcox and David Harrison of the Division of Cardiology have been studying the effect of pravastatin on the functioning of the endothelium, the thin lining that coats the arteries. Healthy endothelium releases nitric oxide synthase, an enzyme essential for the production of nitric oxide that causes arteries to dilate and enable normal blood flow. Arteries that have narrowed as a result of atherosclerosis have a dysfunctional endothelium that produces insufficient amounts of the enzyme. As a result, the diseased arteries constrict.
In the monkeys treated with pravastatin, Wilcox and Harrison measured a distinct improvement in the production of nitric oxide synthase compared to the control group.
"This suggests that pravastatin is improving the health of the endothelium," said Wilcox. "If normal functioning of the endothelium can be restored, atherosclerotic development might be reduced, thus lowering the risk of deadly blood clots forming."
In another study, Wilcox has been examining the ability of pravastatin to prevent "restenosis," or a renarrowing of the artery following balloon angioplasty.
Angioplasty improves blood flow in atherosclerotic vessels by tearing the plaque and artery. In this injured state, the artery quickly begins the process of repairing itself as cells in its walls proliferate. If they multiply too much, however, a new plaque forms-the restenosis lesion-that can block blood flow once again.
Convention has held that the restenosis lesion forms from smooth muscle cells that migrate from the arterial wall into the center of the vessel. Wilcox has instead found evidence that the cells come from the connective tissue surrounding the exterior of the artery. The prospect that the statins could reduce the prevalence of restenosis could potentially translate into a savings of hundreds of millions of dollars in health care costs.
"Our analysis of the arteries in the cynos should help us to better understand what's going on and if the statins prevent smooth muscle proliferation," said Wilcox. To model this process, he and his team have actually performed balloon angioplasty on an experimental sample of the monkeys, administering pravastatin to the animals for 30 days before and after the surgery.
Much more about the genetic processes underlying atherosclerosis is expected to be learned after intensive examination of the monkeys' arteries and major vessels.
In the final analysis, though, one question that will remain unanswered is why the cynos, despite being reared on the same diet, have different cholesterol levels and ultimately varying degrees of atherosclerotic development.
"This is a phenomenon that we see in people as well," said
Wilcox. "Unfortunately, we don't yet have the tools to address that