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August 30, 1999

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Scientists Suggest Genetic Shutdown Links Estrogen, Heart Disease

An age-related drop in estrogen may not be the only reason heart disease in women sharply increases after menopause, a new study by Johns Hopkins researchers suggests. A large-scale genetic event that quietly blocks arteries' ability to respond to estrogen may also be at work.

"Our findings could account for the perplexing results of a recent multicenter study that showed many women with existing coronary artery disease get no heart-saving benefit from hormone replacement therapy," says Wendy S. Post, M.D., who led the research team.

The new research, reported in the September edition of the journal Cardiovascular Research, centers on the fact that blood vessels in the heart are dotted with receptors for the hormone estrogen. When the scientists examined genes that direct the production of estrogen receptors (ERs), they discovered a significant difference between the ER genes from healthy heart vessels and those from vessels clogged by atherosclerosis.

In the healthy vessels, a small number of those genes -- around 4 or 5 percent -- were changed by a process called methylation. Methylation is nature's equivalent of taping over a bar code so it can't be read; small molecules attach to a gene's "on switch," a stretch of DNA called the promoter region, and shut the gene down.

But in clogged heart blood vessels, the researchers found almost three times more methylated ER genes -- around 11 percent.

"We've been looking for the link between estrogen, menopause and atherosclerosis," says Post. "Having estrogen receptor genes shut down so tissues can't respond to estrogen appears to be a significant step."

The real significance, Post says, relates to what happens in atherosclerosis. As part of vessel disease, smooth muscle cells in a blood vessel's wall tend to grow out of control -- "not unlike a tumor," says Post. "Normally, estrogen inhibits smooth muscle overgrowth." But, she suggests, in blood vessels unable to respond to estrogen's effects, smooth muscle cells could run rampant, giving blood vessels a hallmark of atherosclerosis.

In their research, Post and her team studied samples of patients' blood vessel and heart tissue normally discarded during coronary bypass surgery or coronary atherectomy, a "roto-rooter"- like process that clears plaque from coronary arteries. They used specialized molecular probes to identify "normal" ER genes and those that were methylated.

"Many studies show women on hormone replacement therapy are at decreased risk for heart disease," says Post. "Our research, while preliminary, could account for the perplexing results of HERS (the Heart and Estrogen/Progestin Replacement Study) which found no protection."

A year ago, when researchers announced the results of HERS, which looked at nearly 3,000 women with existing coronary artery disease, cardiologists were shocked to find replacement hormones apparently offered no protection against heart attack. Because of the new study, Post says, her team will now look at increased methylation in the genes of older women as a possible explanation.

Earlier work by team member Jean-Pierre Issa, M.D., has shown that in the colon, the number of methylated genes increases as a person ages. Also, in colon cancer and other colon tumors, virtually all ER genes are methylated. "Age-associated changes in methylation may link aging with colon cancer early on," says Post; "And we were looking for the same trend with atherosclerosis."

The research was funded by an NIH grant, by the American Heart Association and by a grant from the Bernard Foundation.

Other researchers were Calvin Wilhide, Ph.D., Alan Heldman, M.D., Mark Sussman, M.D., Pamela Ouyang, M.D., Emily Milliken and Pascal Goldschmidt-Clermont, M.D. (now at Ohio State University).

Related Web site: http://www.med.jhu.edu/methylation

The article is in the September issue of Cardiovascular Research, vol 43, no.4, pp. 985-991.

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