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1 Department of Pediatrics, Northwestern University, Chicago, IL, USA
2 Department of Biomedical & Pharmaceutical Sciences, The University of Montana, Missoula, MT, USA; International Heart Institute, The University of Montana, Missoula, MT, USA
* To whom correspondence should be addressed. E-mail: stephen.black{at}umontana.edu.
Similar to infants born with persistent pulmonary hypertension of the newborn (PPHN) there is an increase in circulating endothelin-1 (ET-1) and decreased endothelial NO syntahse (eNOS) gene expression in an ovine model of PPHN. These abnormalities lead to vasoconstriction and vascular remodeling. Our previous studies have demonstrated that reactive oxygen species (ROS) levels are elevated in the pulmonary arteries from PPHN lambs and that ET-1 increases ROS production in pulmonary arterial smooth muscle cells (PASMC) in culture. Thus, the objective of this study was to determine if there was a feedback mechanism between the ET-1 mediated increase in ROS in fetal PASMCs and a decrease in eNOS gene expression in fetal pulmonary arterial endothelial cells (PAECs). Our results indicate that ET-1 increased H2O2 levels in fetal FPASMC in an ETA receptor dependent fashion. This was observed in both FPASMC mono-culture and in co-cultures of FPASMC and FPAEC. Conversely, ET-1 decreased H2O2 levels in FPAEC monoculture in an ETB receptor dependent fashion. Furthermore, ET-1 decreased eNOS promoter activity by 40% in FPAEC in co-culture with FPASMC. Promoter activity was restored in the presence of catalase. In FPAEC in mono-culture treated with 0-100µM H2O2, 12µM had no effect on eNOS promoter activity but increased eNOS protein levels by 50%. However at 100µM, H2O2 decreased eNOS promoter activity and protein levels in FPAEC by 79% and 40% respectively. These data suggest a role for SMC-derived H2O2 in ET-1-mediated down-regulation of eNOS expression in children born with PPHN.
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