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Cross talk between NADPH oxidase and autophagy in pulmonary artery endothelial cells with intrauterine persistent pulmonary hypertension

Div. of Neonatology, Dept. of Pediatrics, Medical College of Wisconsin, Wauwatosa, WI 53226, USA.
AJP Lung Cellular and Molecular Physiology (Impact Factor: 4.04). 01/2012; 302(7):L651-63. DOI: 10.1152/ajplung.00177.2011
Source: PubMed

ABSTRACT Autophagy is a process for cells to degrade proteins or entire organelles to maintain a balance in the synthesis, degradation, and subsequent recycling of cellular products. Increased reactive oxygen species formation is known to induce autophagy. We previously reported that increased NADPH oxidase (NOX) activity in pulmonary artery endothelial cells (PAEC) from fetal lambs with persistent pulmonary hypertension (PPHN) contributes to impaired angiogenesis in PPHN-PAEC compared with normal PAEC. We hypothesized that increased NOX activity in PPHN-PAEC is associated with increased autophagy, which, in turn, contributes to impaired angiogenesis in PPHN-PAEC. In the present study, we detected increased autophagy in PPHN-PAEC as shown by increased ratio of the microtubule-associated protein 1 light chain (LC3)-II to LC3-I and increased percentage of green fluorescent protein-LC3 punctate positive cells. Inhibiting autophagy by 3-methyladenine, chloroquine, and beclin-1 knockdown in PPHN-PAEC has led to decreased autophagy and increased in vitro angiogenesis. Inhibition of autophagy also decreased the association between gp91(phox) and p47(phox), NOX activity, and superoxide generation. A nonspecific antioxidant N-acetylcysteine and a NOX inhibitor apocynin decreased autophagy in PPHN-PAEC. In conclusion, autophagy may contribute to impaired angiogenesis in PPHN-PAEC through increasing NOX activity. Our results suggest that, in PPHN-PAEC, a positive feedback relationship between autophagy and NOX activity may regulate angiogenesis.

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Available from: Yang Shi, Aug 31, 2015
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    • "In this study, we sought to characterize the effect of chloroquine on BMPR-II levels in the endothelium. Recent research using PAECs from a persistent pulmonary hypertension model in fetal lambs described impaired angiogenesis which could be rescued by chloroquine inhibition of autophagy (38). However, as yet there is no literature describing the regulation of BMPR-II by chloroquine in endothelial cells. "
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    • "Excessive oxidative stress, on the other hand, promotes cell apoptosis by activating the death-related pathway, known as type II programmed cell death (PCD). In persistent pulmonary hypertension (PPHN), autophagy of the pulmonary artery endothelial cells (PAECs) is proapoptotic and forms a positive feedback loop with Nox-derived ROS [76]. "
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