The condition causes a progressive increase in blood pressure in the main pulmonary artery, which originates in the heart's right ventricle and delivers blood to the lungs. The rise in pressure impairs heart function by enlarging the right ventricle, potentially leading to heart failure.
Published in the Sept. 15 issue of the American Journal of Respiratory and Critical Care Medicine, the preclinical study shows that in rats, estrogen treatment can reverse the progression of pulmonary hypertension to heart failure and can restore lung and ventricle structure and function.
The disease progresses slowly, so most patients don't seek treatment until major symptoms occur, such as shortness of breath, dizziness and fainting. According to researchers, current medication for pulmonary hypertension only temporarily reduces the disease's severity. For advanced pulmonary hypertension, there are fewer options, and the condition often necessitates a lung transplant.
"Unfortunately, up until now, there hasn't been an ideal pharmacological therapy to treat advanced pulmonary hypertension," said senior study author Mansoureh Eghbali, Ph.D., an assistant professor of anesthesiology at the David Geffen School of Medicine at UCLA who has a strong background in studying the role of gender and estrogen in cardiovascular diseases. "We hope that this early study may offer insight into new therapies."
The UCLA team found that by treating rats with severe pulmonary hypertension with low doses of estrogen, they were able to prevent the disease from progressing to right-ventricular heart failure; this did not happen in untreated rats.
Systolic blood pressure and ejection fraction — the volume of blood being pumped out of the heart's right chamber with each heart beat — also improved. Tests showed that lung weight, which can increase with the disease and resulting heart-ventricle enlargement, was also corrected. After 10 days of estrogen treatment, function returned to an almost normal state.
The researchers stopped the estrogen therapy after 10 days but continued to observe some of the treated rats. They tracked the continued improvement and found almost full restoration of systolic blood pressure and ejection fraction to normal levels after an additional 12 days.
"We were surprised to find this continued benefit, even after we stopped the estrogen treatment," said the study's first author, Dr. Soban Umar, a UCLA Department of Anesthesiology researcher who has studied pulmonary hypertension and right-ventricular heart failure and is a key member of Eghbali's laboratory team. "These findings suggest that even short-term estrogen therapy may suffice to reverse the disease."
All rats with severe pulmonary hypertension that were treated with estrogen survived by the study's end. Only 25 percent of the untreated rats survived.
The team also explored how estrogen could work in reversing the disease by studying several cellular and molecular mechanisms.
They found that the number of inflammatory cells in rats with pulmonary hypertension increased five-fold, compared with normal rats. In the animals treated with estrogen, this was reversed to normal. The team found that estrogen reduced regulation of a pro-inflammatory gene that also plays a key role in disease development caused by pulmonary hypertension. They also found that estrogen had an inhibitory effect on lung fibrosis.
In addition, the team observed that estrogen therapy restored blood vessels in the lungs and right ventricle whose loss is associated with the disease.
Further study identified that estrogen exerts its biological effects on pulmonary hypertension through a receptor called estrogen receptor beta, a protein that regulates estrogen's activity in the body.
"Estrogen appears to work through an interplay of several factors, including suppression of lung inflammation and fibrosis, as well as reversal of ventricle enlargement," Eghbali said. "We may be able to utilize estrogen receptor beta in the development of future therapies to stimulate estrogen activity to treat pulmonary hypertension."
Researchers had also tested estrogen receptor alpha, the other receptor that controls estrogen activity, but found that it wasn't as effective in treating pulmonary hypertension.
Eghbali added that estrogen receptor beta may prove to be a favorable therapeutic target, since this receptor may require only a short treatment duration and low dosage and has less pro-estrogenic effects on the breasts and uterus than estrogen receptor alpha.
Pulmonary hypertension affects mostly younger women, despite the fact that females in this age group should be under the protective benefits of natural estrogen produced by the body, Eghbali said.
"These patients may have a genetic mutation that is interfering in how estrogen receptor beta directs estrogen activity that is leading to pulmonary hypertension," she said.
Her team's next step is to explore these genetic questions. Currently, Umar and Eghbali are collaborating with UCLA pulmonary hypertension physicians to investigate gender-related issues and to define the role of estrogen in patients with this deadly disease.
The study was funded by the National Institutes of Health.
Additional authors included Andrea Lorga, Humann Matori, Rangarajan Nadadur, Jingyuan Li and Federica Maltese of the department of anesthesiology in the division of molecular medicine at the Geffen School of Medicine, and Arnoud van der Laarse of the department of cardiology at Leiden University Medical Center in the Netherlands.
For more news, visit the UCLA Newsroom and follow us on Twitter.
Rachel Champeau | EurekAlert!
How cancer metastasis happens: Researchers reveal a key mechanism
19.01.2018 | Weill Cornell Medicine
Researchers identify new way to unmask melanoma cells to the immune system
17.01.2018 | Duke University Medical Center
On the way to an intelligent laboratory, physicists from Innsbruck and Vienna present an artificial agent that autonomously designs quantum experiments. In initial experiments, the system has independently (re)discovered experimental techniques that are nowadays standard in modern quantum optical laboratories. This shows how machines could play a more creative role in research in the future.
We carry smartphones in our pockets, the streets are dotted with semi-autonomous cars, but in the research laboratory experiments are still being designed by...
What enables electrons to be transferred swiftly, for example during photosynthesis? An interdisciplinary team of researchers has worked out the details of how...
For the first time, scientists have precisely measured the effective electrical charge of a single molecule in solution. This fundamental insight of an SNSF Professor could also pave the way for future medical diagnostics.
Electrical charge is one of the key properties that allows molecules to interact. Life itself depends on this phenomenon: many biological processes involve...
At the JEC World Composite Show in Paris in March 2018, the Fraunhofer Institute for Laser Technology ILT will be focusing on the latest trends and innovations in laser machining of composites. Among other things, researchers at the booth shared with the Aachen Center for Integrative Lightweight Production (AZL) will demonstrate how lasers can be used for joining, structuring, cutting and drilling composite materials.
No other industry has attracted as much public attention to composite materials as the automotive industry, which along with the aerospace industry is a driver...
Scientists at Tokyo Institute of Technology (Tokyo Tech) and Tohoku University have developed high-quality GFO epitaxial films and systematically investigated their ferroelectric and ferromagnetic properties. They also demonstrated the room-temperature magnetocapacitance effects of these GFO thin films.
Multiferroic materials show magnetically driven ferroelectricity. They are attracting increasing attention because of their fascinating properties such as...
08.01.2018 | Event News
11.12.2017 | Event News
08.12.2017 | Event News
19.01.2018 | Materials Sciences
19.01.2018 | Health and Medicine
19.01.2018 | Physics and Astronomy