胆固醇副产品能阻断雌激素对心脏的有益作用

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Cholesterol byproduct blocks heart health benefits of estrogen

DALLAS, Sept. 18: New findings by UT Southwestern Medical Center researchers show that a byproduct of cholesterol metabolism interferes with the beneficial effects estrogen has on the cardiovascular system, providing a better understanding of the interplay between cholesterol and estrogen in heart disease, says Eurekalert press release.

The results of the study, available online and in the October issue of the journal Nature Medicine, also may explain why hormone replacement therapy fails to protect some postmenopausal women from heart disease, said Dr. David Mangelsdorf, chairman of pharmacology and senior author of the paper.

The researchers found that in rodents, a molecule called 27-hydroxycholesterol, or 27HC, binds to the same receptors in the blood vessels of the heart to which estrogen binds.

The normal result of this estrogen binding is that blood vessel walls remain elastic and dilated, and damage to the vasculature is repaired, among other heart-protective effects. Other research has shown that postmenopausal women – who no longer produce estrogen – lose this protective action and become more susceptible to heart disease.

Based on their animal studies and other experiments, the UT Southwestern researchers determined that when estrogen levels dropped relative to the amount of 27HC circulating in the blood, 27HC reacted and bound to the estrogen receptors in the cardiovascular system and blocked their protective function, primarily by inhibiting the production of nitric oxide. Nitric oxide mediates smooth muscle relaxation in blood vessels, aids cell growth and repair, and prevents thrombosis. Reduced levels of nitric oxide in blood vessels has been linked with high cholesterol and diabetes.

In animals fed a high-fat, high-cholesterol diet, both cholesterol and 27HC levels were elevated.

“We found that 27HC can effectively inhibit estrogen function in vascular tissue by binding to estrogen receptors,” said Dr. Mangelsdorf, a Howard Hughes Medical Institute investigator at UT Southwestern. “This study not only illustrates the damaging effects high cholesterol has on the heart but also supports the notion that the relative levels of 27HC and estrogen in the vasculature are contributing factors to the risk for cardiovascular disease.”

In normal premenopausal women, the amount of 27HC generated from cholesterol is relatively low compared to the level of estrogen circulating in the blood, leading to enhanced cardiovascular protection. In contrast, when the level of 27HC is higher relative to estrogen, such as during the postmenopausal period or as a consequence of high cholesterol, the researchers speculate that 27HC out-competes estrogen to bind with estrogen receptors, blocking the function of the receptors and resulting in a loss of protection.

“This model may help explain why women are better protected than men from cardiovascular disease until they reach menopause,” said Dr. Mangelsdorf.The findings also may help explain why a large clinical trial that evaluated certain hormone replacement therapies (HRT) in postmenopausal women – a component of the 15-year Women’s Health Initiative – had to be halted in 2002 when the hormones appeared to increase a woman’s risk of heart disease.“In the Women’s Health Initiative research program, the women who began taking HRT were an average of 13 years postmenopause,” Dr. Manglesdorf said. “By the time they started taking this estrogen again, the damage caused by 27HC binding to the estrogen receptors in the cardiovascular system may already have occurred. Once you lose estrogen’s protection for such an extended period of time, you can’t get it back.”

The researchers also found that 27HC works predominantly on estrogen receptors in the cardiovascular system. When it binds to estrogen receptors in other tissues, such as reproductive tissues, it has no effect on their reproduction-related functions. This property of 27HC makes it a “selective estrogen receptor modulator,” or SERM, the first such naturally occurring molecule known to exhibit such selectivity.

“This molecule is remarkable in its selectivity for the vasculature,” Dr. Mangelsdorf said. “These findings also validate the estrogen receptor as a possible drug target for manufactured SERMs.”###Other UT Southwestern researchers involved in the study were: lead author Dr. Michihisa Umetani, instructor of pharmacology; Dr. Hideharu Domoto, former postdoctoral researcher in pharmacology; Dr. Andrew Gormley, former postdoctoral research fellow in pediatrics; Ivan S. Yuhanna, senior research associate in pediatrics; Dr. Carolyn Cummins, HHMI research associate in pharmacology; and Dr. Philip W. Shaul, professor of pediatrics. Researchers from the New York University School of Medicine and the National Institute of Environmental Health Sciences also contributed.

The work was supported by the Howard Hughes Medical Institute, the Robert A. Welch Foundation and the National Institutes of Health.

胆固醇代谢产物能阻断雌激素对心脏的有益作用


Eurekalert达拉斯9月18日报道：得克萨斯大学西南医学中心研究人员的最新发现表明一种胆固醇代谢产物可妨碍雌激素对心血管系统的有益作用，此项研究结果将发表在十月份的《自然医学》杂志上。

雌激素与血管内的受体结合可使血管壁保持弹性和处于扩张状态，并与其它心脏保护机制一同修复受损的脉管系统。

研究人员发现在啮齿类动物中有一种被称为27-羟基胆甾醇或27HC的小分子，它可与心血管内的雌激素受体结合。用高脂肪、高胆固醇食物饲养的动物，其胆固醇与27HC的水平均升高。

研究人员通过动物实验等确定，当雌激素水平相对于血循环中27HC的量降低到一定程度时，27HC与心血管系统中雌激素受体反应并与之结合，主要通过抑制一氧化氮的产生而阻断雌激素的保护作用。而一氧化氮可介导血管平滑肌松弛，辅助细胞生长和修复，防止血栓形成。

绝经前女性血循环中由胆固醇代谢产生的27HC的量与雌激素水平相比相对较低，对心血管的保护作用增强。相反，如在绝经期后或高胆固醇血症27HC水平与雌激素相比相对较高时， 27HC就会与雌激素竞争结合雌激素受体，阻断受体的功能，从而失去了对心血管的保护作用。

“这一模型有助于说明为什么更年期前的女性比男性能更好地防御心血管疾病，”药理系主任、此文的责任作者David Mangelsdorf 博士说。该发现也有助于说明为什么作为15年妇女健康启动项目的一部分，用来评估绝经期后妇女激素替代疗法（HRT）的大规模临床试验不得不在2002年提前终止，因为这些激素使妇女患心脏病的风险增加。“在妇女健康启动项目研究计划中，妇女是在平均绝经期后13年开始进行HRT的，”Manglesdorf 博士说。“在她们重新开始服用雌激素之前， 27HC与心血管系统中雌激素受体结合产生的损害作用可能已经发生了。一旦在这么长的时间里失去了雌激素的保护作用，所产生的损害就难以恢复了。”

27HC主要与心血管系统中的雌激素受体作用。27HC的这一特性使它成为一个天然的“选择性雌激素受体调节器，”或简称为SERM。这些发现也表明了雌激素受体有可能成为人工SERM作用的药物靶点。