Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Pulmonary hypertension in children may result from reduced activity of gene regulator

09.03.2009
Too little activity by gene regulators called PPARs appears to be a major player in the irreversible lung damage that can occur in children with heart defects, researchers say.

If they are right, drugs already under study to boost PPAR signaling in adults with lung injuries, may help these infants restore a healthy balance of blood vessel dilation and contraction, preventing the remodeling that transforms flexible blood vessels into rigid pipes and the pulmonary hypertension that often results.

"These drugs might be another therapy where you can treat some of the underlying mechanisms that have become deranged and reset the clock; essentially you can help the body go back to normal," said Dr. Stephen Black, a cell and molecular physiologist at the Medical College of Georgia's Vascular Biology Center.

About 1 percent of children are born with a heart defect with half requiring surgery. Improved surgical and medical treatments have improved survival rates for these children. Still their risk of related lung disease also can be deadly, researchers say as the high blood flow these defects produce pummels the lungs, turning flexible pulmonary blood vessels into rigid pipes, said Dr. Black, who co-directs the Cardiovascular Discovery Institute in the MCG School of Medicine.

Dr. Black and his colleague, Dr. Jeffrey Fineman, a whole-animal physiologist and physician at the University of California, San Francisco, want to understand the molecular mechanisms that disrupt regulatory mechanisms of the inner lining of blood vessels, or endothelium, and put children at increased risk. Dr. Black is principal investigator on two new National Institutes of Health grants and co-investigator on a third with Dr. Fineman to help dissect the dysregulation.

In a surgically created animal model of a congenital heart defect that causes too much pulmonary blood flow, they have already shown PPARs – peroxisome proliferator-activated receptors – are down regulated. In these lambs, whose four-chambered hearts are essentially identical to humans, agonists to boost PPAR activity prevent the usual endothelial dysfunction that occurs in the first few weeks after birth. Conversely, PPAR antagonists cause endothelial dysfunction without the underlying heart defect.

At its core, endothelial dysfunction is decreased ability of blood vessels to dilate and increased ability to thicken. That's just what MCG and UCSF researchers have seen in their animal model: increased expression of genes that cause blood vessels to constrict and reduced expression of those that enable dilation. They also are learning that the imbalance results from synergistic factors.

There's increased presence of reactive oxygen species which scavenge nitric oxide, a powerful dilator. There's also more asymmetric dimethyl arginine, or ADMA, which inhibits nitric oxide production, making bad matters worse. Nitric oxide synthase uses arginine to make nitric oxide and ADMA, an arginine analogue, can bind to the nitric oxide precursor so it instead becomes a source for free radical generation. Genes that regulate transfer of carnitine, an amino acid that regulates energy metabolism in the cell, also are out of whack so the cell's energy plants, or mitochondria, don't produce adequate energy but do start producing free radicals. Interestingly, the researchers have evidence that the carnitine genes are regulated by PPAR. And, they have documented an early increase in ADMA in their animal model and are studying its impact on cell signaling.

The way it's supposed to work is all about balance: the same amount of blood that comes into the heart being pumped to the lungs to pick up oxygen then going back to the heart to be pumped to the body. In their animal model, and in some children with heart defects, three times more blood goes back to the lungs than to the body. The shear force this exerts on the blood vessel lining sets in motion the resulting imbalance of contraction, dilation and more.

When a heart defect is the cause, pulmonary hypertension develops the first few weeks after birth, when previously idle lungs start getting hammered with excessive blood volume. In one of the worst case scenarios, pulmonary hypertension can preclude surgery to repair the heart defect that's causing the problem.

Other babies don't have heart defects but still are in deep and immediate trouble at birth. One reason is meconium aspiration, when stool in the amniotic fluid gets inside a baby's lungs before birth so lungs can't function properly afterward.

Dr. Black suspects that underlying mechanisms that cause endothelial dysfunction and pulmonary hypertension in both scenarios have PPAR in common.

If all continues to go well, the researchers hope to begin clinical trials of PPAR agonists in 2010.

Toni Baker | EurekAlert!
Further information:
http://www.mcg.edu

More articles from Health and Medicine:

nachricht How cancer metastasis happens: Researchers reveal a key mechanism
19.01.2018 | Weill Cornell Medicine

nachricht Researchers identify new way to unmask melanoma cells to the immune system
17.01.2018 | Duke University Medical Center

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Artificial agent designs quantum experiments

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...

Im Focus: Scientists decipher key principle behind reaction of metalloenzymes

So-called pre-distorted states accelerate photochemical reactions too

What enables electrons to be transferred swiftly, for example during photosynthesis? An interdisciplinary team of researchers has worked out the details of how...

Im Focus: The first precise measurement of a single molecule's effective charge

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...

Im Focus: Paradigm shift in Paris: Encouraging an holistic view of laser machining

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...

Im Focus: Room-temperature multiferroic thin films and their properties

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...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

10th International Symposium: “Advanced Battery Power – Kraftwerk Batterie” Münster, 10-11 April 2018

08.01.2018 | Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

 
Latest News

Let the good tubes roll

19.01.2018 | Materials Sciences

How cancer metastasis happens: Researchers reveal a key mechanism

19.01.2018 | Health and Medicine

Meteoritic stardust unlocks timing of supernova dust formation

19.01.2018 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>