Authors of the report in the latest issue of Nature ( March 21, 2002), "Oestrogen protects FKBP12.6 mice from cardiac hypertrophy," used the newly developed mouse "model" for an enlarged heart muscle to help explain estrogen's important role in preventing female cardiac hypertrophy -- extreme stress on the heart that is an early sign of congestive heart failure. However, the researchers say, much more research is needed into the complex causes of heart-muscle enlargement, a condition that leads to cardiac hypertrophy.
But results of the mouse studies, they say, are clear:
o Among mice genetically engineered for a predisposition to an enlarged heart muscle, male mice develop early signs of cardiac hypertrophy similar to the potentially fatal human condition, whereas similarly engineered female transgenic mice do not.
o Unless, that is, the female mice are treated with a drug to block natural estrogen production. By being unable to produce estrogen, the female mice had the same kind of cardiac hypertrophy as did the male mice -- indicating that estrogen production protects the females but not the males.
Referring to recent evaluations of estrogen replacement therapy for postmenopausal women, Michael Kotlikoff, professor and chair of clinical sciences at Cornell, says: "This finding correlates well with epidemiological data indicating an increase in the incidence of cardiomegaly (enlargement of the heart) in women after menopause. We are hopeful that these mice will provide insight to the processes leading to cardiac enlargement and the role that estrogen plays in ameliorating this process."
In addition to Kotlikoff, whose laboratory in the College of Veterinary Medicine at Cornell studies calcium channel signaling in muscle cells, authors of the Nature report include: Vanderbilt researchers Sidney Fleischer, Dong-Sheng Cheng, Julio A. Copello, Loice H. Jeyakumar, Tadashi Inagaml and Mark A. Magnuson; Mei Lin Collier of the University of Pennsylvania School of Veterinary Medicine; and Yong-Xiao Wang, Guang-Ju Ji, Ke-Yu Deng and Hong-Bo Xin of Cornell.
Now an assistant professor of biomedical sciences in Cornell's veterinary college, Xin was a postdoctoral researcher in Vanderbilt's Department of Biological Sciences when he developed the so-called knock-out mouse (or null mouse) that lacks the gene to produce the binding protein FKBP12.6. The protein is associated with receptors in heart muscle cells that signal for the contraction of muscle cells when calcium ions pass through channels, causing the heart to pump blood.
The Cornell-Vanderbilt mouse studies show for the first time how FKBP12.6 regulates the release of calcium in muscle-cell signaling, and also suggested that estrogen can protect mice -- and perhaps humans, too -- from the consequences of poorly regulated calcium release.
"When we examined calcium release in heart cells from knock-out mice, we found an abnormal calcium release process in both male and female mice," Kotlikoff says. "Calcium-release events were lengthened and increased in size in knock-out mice," he says, describing a kind of calcium overload to the signaling channels. "This is the first demonstration that FKBP12.6 participates in excitation/contraction coupling in the normal heart."
More surprising to the researchers, however, was the difference between male and female mice, both lacking the gene for FKBP12.6. Even though heart cells in female and male mice had the same genetic defect and the same degree of abnormal calcium release, females were somehow protected from developing cardiac enlargement in response to the defect.
"We wondered whether the factor protecting the female hearts was estrogen," Kotlikoff recalls. "And, indeed, when we blocked estrogen receptors in female knock-out mice [with the drug tamoxifen], they developed cardiac hypertrophy just like the males."
For years, estrogen replacement therapy has been prescribed to postmenopausal women for a variety of conditions, including stroke and heart disease, osteoporosis and hot flashes, although recent epidemiological studies have questioned the hormone's effectiveness in averting some problems, including stroke. Tamoxifen sometimes is prescribed to block estrogen production in women diagnosed with estrogen-related cancer, but that therapy also is somewhat controversial. Virtually all medical authorities agree that uncontrolled cardiac hypertrophy, without major intervention such as a transplant, results in death from heart failure.
Kotlikoff says that investigators need to learn how and why estrogen affects the abnormal growth of the heart muscle cells, called myocytes, as well as other kinds of body cells. He suggests that more detailed studies might find new evidence linking estrogen, blood pressure and hypertension. The body's system of cell-signaling triggers, receptors, channels, genes and regulatory mechanisms, he says, is "a very complex complex."Vanderbilt's Fleischer says: "With the knock-out mice, we have calcium signaling defined in a way that causes cardiac hypertrophy. We should be able to sort out the molecular signaling events that lead to this condition. It may also prove possible to slow down and even reverse the hypertrophy [in mice]. Chances are, it will be similar in humans."
The studies were supported by grants from the National Institutes of Health and by a Discovery Grant from Vanderbilt University.
Journal
Nature