Abnormal pulmonary vascular relaxation and increased reactivity, early manifestations of pulmonary vascular disease, are responsible for significant morbidity in infants and children with common congenital heart defects that cause increased pulmonary blood flow. Beginning immediately after birth, the pulmonary vasculature in these patients is subjected to pathologic mechanical forces, including chronically increased shear stress, which results in early functional abnormalities of the vascular endothelium. Importantly, these functional abnormalities, which are thought to include decreases in bioavailable nitric oxide (NO) and increases in oxidative stress, occur prior to the development of well-described vascular remodeling. Unfortunately, little is known about the molecular mechanisms that mediate this process, particularly those that transduce the abnormal shear forces associated with increased pulmonary blood flow into abnormal vascular function and reactivity. Peroxisome proliferator-activated receptors (PPARs), members of a nuclear hormone receptor superfamily, are emerging as integral mediators of a wide array of disease processes, including vascular disorders. In fact, a recent study found that PPAR?, a member of the PPAR family, is decreased in patients with severe pulmonary hypertension and that shear stress decreases endothelial cell PPAR? expression. Interestingly, Kruppel-like Factor 2 (KLF2), a zinc finger protein transcriptional factor, was recently shown to be uniquely induced by flow in human lung endothelial cells, and to be a potent inhibitor of PPAR? expression in adipose tissues. However, the mechanisms by which PPAR3 and KLF2 may affect the development of pulmonary vascular disease are not understood. Utilizing our ovine model of a congenital heart defect with increased pulmonary blood flow, created by the in utero placement of an aorto-pulmonary vascular graft, we have generated preliminary data to support our overall hypothesis that disruption of PPAR? signaling secondary to a H2O2-induced, flow-mediated activation of LKLF2, results in increased ROS and decreased bioavailable NO, and thereby fundamentally participates in the development of pulmonary vascular disease under conditions of increased pulmonary blood flow. In this proposal, a series of studies that integrate anatomic, biochemical, cellular, and molecular techniques, will be undertaken in order to investigate this hypothesis. With a clinically relevant large animal model as a foundation, the data generated from this proposal could translate readily into novel and efficacious clinical therapies for patients suffering from pulmonary vascular disease.
Infants and children afflicted with congenital heart defects with increased pulmonary blood flow, suffer morbidity and mortality from the development of pulmonary vascular disease with abnormal pulmonary vascular reactivity. Understanding the controlling mechanisms of this pathology might improve the clinical outcome, that is the quality of life and survival, of this vulnerable population. In this proposal, we will study the novel potential role of LKLF2 and PPAR? in this pathology. With a clinically relevant large animal model as a foundation, the data generated from this proposal could translate readily into novel and efficacious clinical therapies for patients suffering from pulmonary vascular disease.
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