Persistent pulmonary hypertension of the newborn (PPHN) is a condition that results from failure of pulmonary vasodilation to occur at birth. The affected infants are hypoxemic and have increased risks of mortality and long-term disabilities. Studies in a fetal lamb model of PPHN, induced by prenatal ductal constriction demonstrated a decrease in NO release and increase in oxidative stress in pulmonary arteries. Activation of NADPH oxidase and uncoupled activity of endothelial nitric oxide synthase (eNOS) are sources of superoxide (O2?-) in the pulmonary arteries in PPHN. Mitochondrial oxygen consumption is an important source of O2?- generation in vascular cells. Increase in O2 availability and oxidative phosphorylation at birth may lead to increased reactive oxygen species (ROS) in mitochondria. However, the contribution of mitochondrial ROS to oxidative stress in PPHN is unknown. Exposure to ATP, a NOS agonist, and postnatal oxygen tension stimulate the association of eNOS with the mitochondrial outer membrane protein, porin in normal fetal lamb pulmonary artery endothelial cells (PAEC). Targeted NO release in this location regulates the rate of oxidative phosphorylation to decrease O2?- production in normal fetal PAEC. The expression of manganese superoxide dismutase (MnSOD) is also decreased in PPHN. We propose to investigate the novel hypothesis that decreased targeting of eNOS to mitochondrial outer membrane and decreased expression of MnSOD lead to excess generation and decreased quenching of mitochondrial O2?-. The mitochondrial O2?- in turn impairs pulmonary vasodilation at birth. The broad specific aims of the proposed studies are to (1) Investigate the alterations in eNOS-mitochondrial interactions and MnSOD expression in PPHN and its effect on O2 consumption, NO and O2?- levels during postnatal transition of PAEC, (2) Investigate the mechanism of altered eNOS targeting to mitochondria in PPHN and (3) investigate the role of mitochondrial oxidative stress in the impaired pulmonary vasodilation and oxygenation during birth-related transition in PPHN. Studies will be done in PAEC and pulmonary arteries harvested from lambs with prenatal ligation of ductus arteriosus (PPHN) and in sham ligation controls. Studies will be also done in intact fetal lambs with or without PPHN delivered at term to investigate the role of mitochondrial O2?- in the transition of pulmonary circulation and oxygenation at birth. These studies will identify an important new source of oxidative stress in PPHN. These observation may lead to new targeted therapies to improve vasodilation and oxygenation in PPHN.
An increase in blood flow to the lung occurs at birth to help establish gas exchange by the lung during postnatal life. Failure of this adaptation results in persistent pulmonary pulmonary hypertension in the newborn infant (PPHN), associated with severe hypoxemia and increased risk of death and disability. The proposed studies will investigate the mechanisms and potential new therapies for this disease.
|Afolayan, Adeleye J; Teng, Ru-Jeng; Eis, Annie et al. (2014) Inducible HSP70 regulates superoxide dismutase-2 and mitochondrial oxidative stress in the endothelial cells from developing lungs. Am J Physiol Lung Cell Mol Physiol 306:L351-60|
|Cohen, Susan S; Powers, Bethany R; Lerch-Gaggl, Alexandra et al. (2014) Impaired cerebral angiogenesis in the fetal lamb model of persistent pulmonary hypertension. Int J Dev Neurosci 38:113-8|
|Teng, Ru-Jeng; Rana, Ujala; Afolayan, Adeleye J et al. (2014) Nogo-B receptor modulates angiogenesis response of pulmonary artery endothelial cells through eNOS coupling. Am J Respir Cell Mol Biol 51:169-77|
|Teng, Ru-Jeng; Du, Jianhai; Afolayan, Adeleye J et al. (2013) AMP kinase activation improves angiogenesis in pulmonary artery endothelial cells with in utero pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 304:L29-42|
|Konduri, Girija G; Bakhutashvili, Ivane; Eis, Annie et al. (2013) Antenatal betamethasone improves postnatal transition in late preterm lambs with persistent pulmonary hypertension of the newborn. Pediatr Res 73:621-9|
|Teng, Ru-Jeng; Du, Jianhai; Welak, Scott et al. (2012) Cross talk between NADPH oxidase and autophagy in pulmonary artery endothelial cells with intrauterine persistent pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 302:L651-63|
|Teng, Ru-Jeng; Wu, Tzong-Jin; Bisig, C Gaston et al. (2011) Nitrotyrosine impairs angiogenesis and uncouples eNOS activity of pulmonary artery endothelial cells isolated from developing sheep lungs. Pediatr Res 69:112-7|
|Teng, Ru-Jeng; Du, Jianhai; Xu, Hao et al. (2011) Sepiapterin improves angiogenesis of pulmonary artery endothelial cells with in utero pulmonary hypertension by recoupling endothelial nitric oxide synthase. Am J Physiol Lung Cell Mol Physiol 301:L334-45|
|Sampath, Venkatesh; Radish, Aaron C; Eis, Annie L et al. (2009) Attenuation of lipopolysaccharide-induced oxidative stress and apoptosis in fetal pulmonary artery endothelial cells by hypoxia. Free Radic Biol Med 46:663-71|
|Konduri, G Ganesh; Kim, U Olivia (2009) Advances in the diagnosis and management of persistent pulmonary hypertension of the newborn. Pediatr Clin North Am 56:579-600, Table of Contents|
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