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(Last updated 9/14/99)
STUDY SUGGESTS WHY ESTROGEN NOT HELPFUL AGAINST HEART DISEASE
COLUMBUS, Ohio -- Researchers long believed that post-menopausal women undergoing hormone replacement therapy may also gain an added reduction in their risk of developing coronary artery disease. But when a major study released last year showed no such reduction in risk, cardiologists wondered why.
Now, a new study may reveal part of the reason:
The gene that’s responsible for making receptors to the hormone estrogen might be “out of service” as a consequence of atherosclerosis, preventing the formation of the receptor. If there aren’t enough of these receptors within the cells making up the arteries of the cardiovascular system, estrogen cannot provide any preventative effect.
That, at least, seems to be the explanation provided by a study by researchers from Ohio State University and Johns Hopkins Medical Institutions. Their report in the journal Cardiovascular Research blames the missing estrogen benefit on genetic changes caused by a process called DNA methylation.
Pascal Goldschmidt, professor of internal medicine and head of Ohio State’s Heart and Lung Institute and its Division of Cardiology, and director of the study, said the findings may explain the results of earlier attempts to understand estrogen’s role in cardiovascular disease.
Like other researchers investigating heart disease, he was surprised last year by a report in the Journal of the American Medical Association. The first clinical trial testing the effect of hormone replacement therapy on post-menopausal women with known coronary artery disease showed little or no beneficial effect from estrogen.
“It shocked a world that was hoping that estrogen therapy would reduce the risk of coronary artery disease even in women with established atherosclerosis,” Goldschmidt said. “This was the first randomized study and it had the ‘wrong’ results!”
Goldschmidt and his colleagues knew that in colon cancer patients, some tissues expected to be rich with estrogen receptors actually had few or none of them. And since colon cancer seems linked to the aging process, they wondered whether the same situation might also be happening with cardiovascular tissue. The risk of coronary artery disease is known to increase with age.
To test this hypothesis, Wendy Post, then a postdoctoral fellow in Goldschmidt’s laboratory at Johns Hopkins and lead author of the study, took samples from patients undergoing coronary artery bypass surgery. Tissue samples were collected from the patients’ aortas, the saphenous veins and internal mammary arteries, as well as other locations. They also removed samples from plaque buildups within these vessels caused by coronary artery disease.
These were all examined for evidence of DNA methylation, a process in which an enzyme called methyl transferase adds a methyl group to a cytosine molecule within the gene. That change has been shown to prevent the gene from producing estrogen receptors in tissue.
The researchers found ample evidence of methylation in all the samples. In the right atrium of the heart, the extent of methylation seemed to increase with the age of that patient. A similar finding showed up in samples of the plaques, compared to normal tissue.
Surprisingly, the researchers found no homogeneity in the DNA methylation process and consequent loss of estrogen receptor across the cardiovascular system.
“One of the most peculiar things about the way methylation changes this part of the human genome is that it can happen as a mosaic; you can have a segment of vessel that is not methylated immediately adjacent to a highly methylated region,” Goldschmidt said. “That’s very interesting to me.”
He suggests that the loss of estrogen receptors in the tissue may explain why estrogen can’t provide its anticipated benefit to patients. That would be important since researchers believe that some drugs could reduce or prevent methylation from occurring, thereby allowing estrogen to be protective.
Goldschmidt said that future studies need to test that approach. He also said that his team at Ohio State was now looking for evidence of that same methylation in white blood cells compared to other cells involved in coronary artery disease. Since DNA methylation is a potentially reversible process, his team at Ohio State is also looking at ways to restore estrogen responsiveness in the coronary vessels of women with atherosclerosis.
Along with Ohio State’s Goldschmidt, Hopkins researchers Wendy Post, Calvin Wilhide, Alan Heldman, Mark Sussman, Pamela Ouyang, Emily Milliken and Jean-Pierre Issa all worked on the study.
The research was supported by grants from the National Institutes of Health, the American Society of Clinical Oncology, the American Heart Association and the Bernard Foundation.
- Contact: Pascal Goldschmidt, (614) 688-5779
Goldschmidt-1@medctr.osu.edu- Written by Earle Holland, (614) 292-8384; Holland.8@osu.edu