Navigation Links
Pulmonary hypertension in children may result from reduced activity of gene regulator
Date:3/5/2009

AUGUSTA, Ga. - 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.


'/>"/>

Contact: Toni Baker
tbaker@mcg.edu
706-721-4421
Medical College of Georgia
Source:Eurekalert  

Related biology news :

1. Translational research patented first experimental treatment against idiopathic pulmonary fibrosis
2. African-Americans have unique lung cancer risks from chronic obstructive pulmonary disease
3. Gene with probable role in human susceptibility to pulmonary tuberculosis identified
4. Understanding hypertension in African Americans proves elusive
5. Ultra-low-dose aspirin might decrease bleeding severity in portal hypertension
6. Researchers discovery may lead to hypertension treatment
7. Rare genetic mutations protect against hypertension
8. Hypertension treatment effective in reversing vascular damage
9. A single mechanism for hypertension, insulin resistance and immune suppression
10. Blood pressure response to daily stress provides clues for better hypertension treatment
11. Hypertension disparity linked to environment
Post Your Comments:
*Name:
*Comment:
*Email:
Related Image:
Pulmonary hypertension in children may result from reduced activity of gene regulator
(Date:1/21/2016)... , January 21, 2016 ... to a new market research report "Emotion Detection and ... Others), Software Tools (Facial Expression, Voice Recognition and ... - Global forecast to 2020", published by MarketsandMarkets, ... expected to reach USD 22.65 Billion by 2020, ...
(Date:1/20/2016)... --  MedNet Solutions , an innovative SaaS-based eClinical technology ... is pleased to announce the attainment of record-setting corporate ... of the company,s laser focus on (and growing international ... comprehensive, easy-to-use and highly affordable cloud-based technology platform. ... growth achievements in 2015 include: , Record ...
(Date:1/18/2016)... Calif. , Jan. 18, 2016  Extenua ... software that simplifies the use and access of ... and go-to-market partnership with American Cyber.  ... brings extensive experience leading transformational C4ISR and Cyber ... and integrating the latest proven technology solutions," said ...
Breaking Biology News(10 mins):
(Date:2/11/2016)... ... February 11, 2016 , ... ... dedicated to delivering cutting-edge information focused on the development and manufacture of ... become a premier sponsor of the 2016 BioProcess International Awards – Recognizing ...
(Date:2/11/2016)... Florida , February 11, 2016 ... PositiveID Corporation ("PositiveID" or "Company") (OTCQB: PSID), a ... announced today that its Thermomedics subsidiary, which markets ... on its growth plan in January 2016, including ... distributors, increasing sequential monthly sales growth, and establishing ...
(Date:2/11/2016)... ... February 11, 2016 , ... Reichert Technologies, ... continues today to pursue the highest level of accuracy and quality with the ... Refractometer and the AR5 Refractometer. Accurate, reliable and tough enough for the ...
(Date:2/11/2016)... ... February 11, 2016 , ... Global Stem Cells ... in Quito, Ecuador. The new facility will provide advanced protocols and state-of-the-art techniques ... the world. , The new GSCG clinic is headed by four prominent ...
Breaking Biology Technology: