Nav: Home

Protein target may block deadly arterial remodeling in pulmonary hypertension

July 05, 2016

AUGUSTA, Ga. (July 5, 2016) - Pulmonary hypertension is a highly lethal disease that transforms the thin, flexible vasculature of the lungs into thick, dysfunctional blood vessels that can kill.

Scientists believe that a protein highly expressed in the deadly disease is a major culprit as well as a potentially effective new treatment target.

They also have early evidence that a drug already in human studies for liver fibrosis can block or turn around early disease, said Dr. David Fulton, director of the Vascular Biology Center at the Medical College of Georgia at Augusta University.

Fulton and Dr. Scott Barman, pulmonary vascular biologist in the MCG Department of Pharmacology and Toxicology, are principal investigators on a $2.2 million National Institutes of Health grant that will enable them to better understand how the protein galectin-3, or gal-3, helps cause chronic, unhealthy remodeling of the lungs' blood vessels and maybe a way to stop it.

In humans as well as an animal model of the disease, the MCG scientists found increased gal-3 expression particularly in the media, the smooth muscle-rich middle layer of the artery that normally helps give blood vessels strength and flexibility. They've shown that, at least in culture, increasing levels of gal-3 increases unnatural proliferation and survival of these human smooth muscle cells, while silencing gal-3 decreases it.

"Excessive constriction makes the vessels small in the first place; inflammation and remodeling make it a permanent anatomical alteration," said Barman. Right heart failure is typically what kills patients, as that side of the heart is continually overtaxed trying to force blood inside the now-narrowed pulmonary arteries.

"The lung circulation is a high-capacity, low-resistance environment," said Fulton. "Any increase in resistance to blood flow is really damaging." There are a variety of causes. A small percentage of cases are idiopathic, or have no known cause, but known risk factors include heritable genetic mutations; heart disease, including congenital heart disease; emphysema; connective tissue problems such as lupus and scleroderma; obesity; drug side effects; and being female. Symptoms may include shortness of breath, dizziness, fatigue, a racing pulse, even chest pain and pressure. The blood vessels are too tiny and numerous to reopen once damaged. Rather, treatment includes vasodilators that may only extend life by a few years; a lung transplant is the final option. Stopping or somehow reversing the deadly chronic remodeling is the most important target now for scientists like Barman and Fulton.

Gal-3 is implicated as well in cancer, kidney fibrosis and liver fibrosis, diseases in which there also are excessive, unhealthy growth patterns, Barman said. A key goal of their new studies is not only blocking excessive gal-3 levels in pulmonary hypertension, but figuring out why the smooth muscle cells are committed to making the excessive levels. "Where is it coming from and where is it hitting?" Barman said.

They also want to identify epigenetic mechanisms, which underlie enduring changes in cell function that are thought to explain many of the wayward behaviors of cells in disease states. "The smooth muscle cells proliferate, and they don't die," Fulton said.

As they put together the puzzle of how this disease happens, they also are looking at whether the gal-3 inhibitor they have been studying, GR-MD-02, continues to be effective at reversing or stopping the disease. Barman and Fulton are collaborating with Atlanta-based Galectin Therapeutics Inc. and its chief medical officer, Dr. Peter G. Traber, to look further at the gal-3 inhibitor the company developed and is now testing in humans with liver fibrosis.

While the inhibitor doesn't directly lower the gal-3 levels, it blocks its action, Fulton said. Ongoing studies will better determine optimal doses, and they have seen significant early disease reversal with the doses they have used, Barman said. Those findings were presented at the recent American Thoracic Society International Conference.

With treatment, smooth muscle cell growth normalizes, blood vessels relax and their opening, or lumen, widens. The new studies will include more severe models of disease that more closely reflect the stage at which many patients are diagnosed.

"The more we can reverse it later in disease, the more applicable the therapy becomes," Barman said, since by the time patients become symptomatic, the disease is fairly advanced. They also want to better identify the drug's points of action, which are unknown in the pulmonary circulation.

Growth and inflammation are necessary and important short-term in wound healing. "In normal wound healing, that goes away; in pulmonary hypertension, it just consolidates and gets worse," Fulton said, noting that under healthy circumstances, expression of gal-3 is low and its role largely unclear.
-end-


Medical College of Georgia at Augusta University

Related Heart Disease Articles:

Where you live could determine risk of heart attack, stroke or dying of heart disease
People living in parts of Ontario with better access to preventive health care had lower rates of cardiac events compared to residents of regions with less access, found a new study published in CMAJ (Canadian Medical Association Journal).
Older adults with heart disease can become more independent and heart healthy with physical activity
Improving physical function among older adults with heart disease helps heart health and even the oldest have a better quality of life and greater independence.
Dietary factors associated with substantial proportion of deaths from heart disease, stroke, and disease
Nearly half of all deaths due to heart disease, stroke, and type 2 diabetes in the US in 2012 were associated with suboptimal consumption of certain dietary factors, according to a study appearing in the March 7 issue of JAMA.
Certain heart fat associated with higher risk of heart disease in postmenopausal women
For the first time, researchers have pinpointed a type of heart fat, linked it to a risk factor for heart disease and shown that menopausal status and estrogen levels are critical modifying factors of its associated risk in women.
Maternal chronic disease linked to higher rates of congenital heart disease in babies
Pregnant women with congenital heart defects or type 2 diabetes have a higher risk of giving birth to babies with severe congenital heart disease and should be monitored closely in the prenatal period, according to a study published in CMAJ.
Novel heart valve replacement offers hope for thousands with rheumatic heart disease
A novel heart valve replacement method is revealed today that offers hope for the thousands of patients with rheumatic heart disease who need the procedure each year.
Younger heart attack survivors may face premature heart disease death
For patients age 50 and younger, the risk of premature death after a heart attack has dropped significantly, but their risk is still almost twice as high when compared to the general population, largely due to heart disease and other smoking-related diseases The risk of heart attack can be greatly reduced by quitting smoking, exercising and following a healthy diet.
Citrus fruits could help prevent obesity-related heart disease, liver disease, diabetes
Oranges and other citrus fruits are good for you -- they contain plenty of vitamins and substances, such as antioxidants, that can help keep you healthy.
Gallstone disease may increase heart disease risk
A history of gallstone disease was linked to a 23 percent increased risk of developing coronary heart disease.
Americans are getting heart-healthier: Coronary heart disease decreasing in the US
Coronary heart disease is one of the leading causes of death in the United States.

Related Heart Disease Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Digital Manipulation
Technology has reshaped our lives in amazing ways. But at what cost? This hour, TED speakers reveal how what we see, read, believe — even how we vote — can be manipulated by the technology we use. Guests include journalist Carole Cadwalladr, consumer advocate Finn Myrstad, writer and marketing professor Scott Galloway, behavioral designer Nir Eyal, and computer graphics researcher Doug Roble.
Now Playing: Science for the People

#529 Do You Really Want to Find Out Who's Your Daddy?
At least some of you by now have probably spit into a tube and mailed it off to find out who your closest relatives are, where you might be from, and what terrible diseases might await you. But what exactly did you find out? And what did you give away? In this live panel at Awesome Con we bring in science writer Tina Saey to talk about all her DNA testing, and bioethicist Debra Mathews, to determine whether Tina should have done it at all. Related links: What FamilyTreeDNA sharing genetic data with police means for you Crime solvers embraced...