Researchers find potential new use for cholesterol-lowering drugs

Thursday, July 25, 2002

Researchers at Brigham and Women’s Hospital (BWH) have found that statins, drugs widely prescribed to lower cholesterol, may play another key role — preventing the formation of new blood vessels. The finding may lead to new ways to treat diseases that depend on new blood-vessel growth such as cancer, diabetic retinopathy, rheumatoid arthritis and psoriasis. The study is published in the July 26, 2002 edition of Circulation Research.

"Our research found that cholesterol-lowering drugs interfere with the function of a molecule involved in forming blood vessels," said the study’s principal investigator, Jonas Galper, MD, PhD, a cardiovascular physician at BWH and associate professor of medicine at Harvard Medical School.

Specifically, statins work by blocking an enzyme that the liver needs to produce cholesterol. Reducing the low-density form of cholesterol (LDL) is important because it can cause buildup of sticky plaque in arterial walls, a condition called atherosclerosis. Eventually, the plaque may narrow the opening of the artery or may rupture and close off arteries entirely, causing a heart attack or stroke.

In previous studies, scientists have noticed increased growth of blood vessels in the artery’s lining and also inflammation under the plaque site. "It was well established that cholesterol-lowering drugs seemed to prevent the plaque from growing larger," said Dr. Galper. "This suggested that these drugs had a role outside the liver, acting directly on the plaque site, and that one mechanism for this effect might be to prevent new blood-vessel growth."

He theorized that since statins seemed to inhibit the complex biologic process in which cells signal, proliferate and migrate to form new blood vessels, that they might actually prevent new blood-vessel formation, or angiogenesis. To test this hypothesis, his research team devised studies in animals and a cell-culture.

In research on mice, in collaboration with a laboratory at University of California-Los Angeles, they looked at the cornea, the clear eye lens that normally is void of blood vessels. First, they induced blood vessels to grow in the cornea by implanting small plastic pellets containing a blood-vessel growth factor. The cornea became vascularized, red and inflamed. They then used pellets containing both the growth factor and a statin. This time, no blood vessels formed. The statin somehow had interfered with blood vessel formation.

The researchers also studied chick eggs, focusing on the chorioallantoic membrane, a thin tissue that lies just beneath the shell. When a blood-vessel growth factor was introduced to the membrane, small capillary vessels began to form. When a statin was administered with the growth factor, capillary growth was suppressed. Importantly, the dose level of the statin was directly related to the extent that growth was inhibited.

To identify the biologic pathways involved, they created a novel cell-culture system in which human endothelial cells, which line the blood vessel, were grown on a three-dimensional collagen matrix. In the presence of growth factors, tiny vascular tubes formed. Statins inhibited this growth.

They then performed a complex series of molecular experiments that proved angiogeneis is regulated by a small protein called RhoA. They also showed statins interfere with the addition of a lipid molecule to RhoA, which is needed for RhoA to get to the place in the endothelial cell membrane where it does its work.

Overall, this research establishes an important new molecular link between lipid metabolism and angiogenesis. It also suggests that when RhoA is overstimulated by too much lipid binding, more blood-vessel growth will occur — which might cause plaque to enlarge and clog the cardiovascular system, cancer to become more invasive, or excessive vessels and inflammation to form in the retina, bone joints or skin. Further laboratory studies are now underway to determine if these disease processes might be prevented, slowed or reversed by subduing RhoA using appropriate doses of cholesterol-lowering drugs.

"Statins are relatively inexpensive, safe drugs with few side effects," concluded Dr. Galper. "We may have found an important new clinical use for these drugs."

Brigham and Women’s Hospital is a 719-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare System, an integrated health care delivery network. Internationally recognized as a leading academic health care institution, Brigham and Women’s Hospital is committed to excellence in patient care, medical research, and the training and education of health care professionals. The hospital’s preeminence in all aspects of clinical care is coupled with its strength in medical research. A leading recipient of research grants from the National Institutes of Health, Brigham and Women’s Hospital conducts internationally acclaimed clinical, basic and epidemiological studies.