Approximately 1% of children are born with a congenital heart defect, with half requiring medical and/or surgical treatment. Children born with congenital heart defects that result in increased PBF develop abnormal pulmonary vascular reactivity. Although survival for these children has improved they continue to suffer morbidity and late mortality. This is due to the fact that they are at great risk for developing pulmonary vascular disease. In fact, even early pulmonary endothelial dysfunction, with abnormal vascular reactivity, causes significant morbidity and mortality. Using an experimental lamb model of CHD with increased PBF (Shunt) we were the first to identify that decreased interactions between heat shock protein 90 (hsp90) and endothelial NO synthase (eNOS) plays a major role in the reduced nitric oxide (NO) signaling associated with this disease. Our data implicate decreases in hsp90 activity as well as an increase in eNOS nitration in this process. In addition, our published data indicate that the loss of hsp90 activity correlates with the disruption of the eNOS dimeric structure. Based on these data, the overall hypothesis we will test is that eNOS nitration disrupts its interaction with hsp90 leading to dimer disruption and decreased NO generation. Further, we will investigate if stimulating hsp90 activity will restore NO signaling and endothelial function. Our investigations will be carried out in three interrelated, but independent, Aims. We will utilize a translational approach that will integrate biophysical, cellular and whole animal studies. The successful completion of our studies should yield new mechanistic insights and will identify new targets that are amenable to therapeutic intervention.
The incidence of congenital heart defects in the U.S. is ~1 per 100 live births and approximately 50% of these children require medical and/or surgical attention. Although survival for these children has improved they continue to suffer significant morbidity and late mortality, in part because of abnormal vascular reactivity within their lungs. Our studies are designed to increase our understanding of the important signaling molecules that underlie this decrease in endothelial function and could lead to improved survival of children born with congenital heart defects.
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