Mechanism for estrogen's cardiovascular disease protection found

COLUMBUS, Ohio -- Researchers have discovered a new way that the female hormone estrogen uses to inhibit the progress of atherosclerosis in women with cardiovascular disease.

With cardiovascular disease as the No. 1 killer of women in the United States, the finding has strong implications for improving the odds for women at risk for the disease.

Physicians have known that estrogen can raise the level of high density lipoprotein (HDL) -- the "good" cholesterol -- in the blood and therefore cut the risk of heart disease by up to 24 percent. Estrogen can also lower levels of the so-called "bad" cholesterol, low density lipoprotein (LDL) in the blood.

But this new research points to estrogen's role in controlling apoptosis, or programmed cell death, among the cells that line the body's blood vessels. Research teams from Ohio State University and Johns Hopkins Medical Institutions reported their findings in the journal Biochemical and Biophysical Research Communications.

"There are very good reasons to think that estrogen is perhaps the single most potent anti-atherosclerotic agent that we have available," explained Pascal Goldschmidt-Clermont, director of Ohio State's Heart and Lung Institute. Largely because of their estrogen levels, women enjoy an average 10-year delay in the onset of atherosclerosis, he said, compared to men.

"The big question is to understand what the target of estrogen is in the process of disease in the vessel walls," he said. "We decided to look at how the endothelium was damaged and what effect estrogen had on that damaging."

All of the vessels in the body are lined with the endothelium, a single layer of smooth, long-lived endothelial skin cells that cushion the blood as it flows. Damage to these cells has been linked to the onset of blood clots, plaque and cholesterol buildup that can narrow the vessels.

When the endothelial cells are damaged beyond repair, apoptosis begins and the cell dies, its components completely absorbed back into the body.

But researchers found that sometimes apoptosis can proceed either much slower than normal, or it can begin prematurely. In both of these instances, damage to the vessels can occur and with it, an increased risk of developing disease, Goldschmidt-Clermont said.

"Instead of it being a rapid, well-programmed process, apoptosis can then become sluggish and cells that are partially apoptotic may stick around longer than they should," he said.

Apoptosis can also be overactive, removing endothelial cells from the vessel walls before they can be replaced, which leaves gaps in the vessel lining while new cells slowly form. That damage can be dangerous since it triggers the formation of clots and lesions within the vessels.

The researchers worked with tissue cultures grown from cells obtained from the aortas of women who were reasonably free of cardiovascular disease and then exposed them to estradiol, a metabolite compound derived from estrogen. They found that:

The estradiol was able to raise the threshold for stress within the cells that would trigger the onset of apoptosis. This effectively halted premature apoptosis in the endothelial cells but did not prevent apoptosis from occurring when cells were damaged beyond recovery. The presence of estradiol increased the endothelial cells' ability to adhere to the structural matrix that supports the vessel lining, reducing the risk of damage to endothelial cells that could trigger disease.

These new findings have important implications for women who are at risk for cardiovascular disease, Goldschmidt-Clermont said.

Post-menopausal women who have coronary artery disease, or who are at high risk for the disease, should be receiving estrogen replacement therapy unless there are strong contraindications against it, he said.

Those contraindications would include women who either have or who are at high risk for developing breast cancer.

Working with Goldschmidt-Clermont were Rene J. Alverez Jr., Sanford J. Gips, Nicanor Moldovan, Calvin C. Wilhide, Emily E. Milliken, Arthur T. Hoang, Ralph H. Hruban, Howard S. Silverman and Chi V. Dang, all at Johns Hopkins. The work was supported by grants from the Bernard Foundation and the Scleroderma Research Foundation.

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Contact: Pascal Goldschmidt-Clermont (614) 688-5779; Goldschmidt.12@osu.edu

Written by Earle Holland (614) 292-8384; Holland.8@osu.edu