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 reports about: > ADMA > MCG > PPAR gamma > PPARs > amniotic fluid > asymmetric dimethyl arginine > black populations > blood flow > blood vessel > endothelial dysfunction > energy metabolism > heart defect > lung injuries > meconium aspiration > molecular mechanism > nitric oxide > pulmonary > pulmonary hypertension
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