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Nitric oxide mediates LC-3-dependent regulation of fibronectin in ductus arteriosus intimal cushion formation

CATHERINE A. E. MASON^*, PETER CHANG^*, CAROLINE FALLERY^* and MARLENE RABINOVITCH^*,,,1

^* Division of Cardiovascular Research, Research Institute, The Hospital for Sick Children,
Departments of Pediatrics, Pathology and Medicine, University of Toronto, Toronto, Ontario, Canada M5G 1X8

¹Correspondence: Division of Cardiovascular Research, The Hospital for Sick Children, 555 University Ave., Toronto, Ontario, Canada M5G 1X8. E-mail: MR{at}sickkids.on.ca

Ductus arteriosus intimal cushion formation is characterized by fibronectin-dependent smooth muscle cell (SMC) migration. Enhanced fibronectin synthesis in ductus SMC is regulated by the interaction of LC-3, a microtubule-associated protein, with an AU-rich element (ARE) in the 3'-untranslated region of fibronectin mRNA, facilitating its recruitment to polyribosomes for translation. Since nitric oxide (NO) is implicated in posttranscriptional gene regulation and is produced in the ductus, we investigated its mechanistic role in LC-3-mediated fibronectin synthesis. NO production was sevenfold higher in ductus vs. aortic SMC (P<0.005) associated with increased neuronal NO synthase (nNOS) expression. The NOS inhibitor L-NMMA decreased fibronectin synthesis by ~45–50% (P<0.05), whereas the NO donor, SNAP, increased ductus fibronectin synthesis ~onefold (P<0.05); neither agent altered fibronectin mRNA levels. Immunoblotting revealed that SNAP increased and L-NMMA reduced a membrane-associated phosphorylated form of LC-3. RNA gel mobility shift assays confirmed that NO enhanced LC-3 binding to the fibronectin mRNA ARE. Our studies indicate a tissue-specific program in the ductus arteriosus whereby elevated nNOS expression and NO production regulate the posttranscriptional increase in fibronectin synthesis required for SMC motility.—Mason, C. A. E., Chang, P., Fallery, C., Rabinovitch, M. Nitric oxide mediates LC-3-dependent regulation of fibronectin in ductus arteriosus intimal cushion formation.

Key Words: extracellular matrix • cell migration • microtubule • atherosclerosis

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