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Mechanism of Endothelin-1 Activation of Map Kinases in Neonatal Pulmonary Vascular Smooth Muscle

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Abstract

Mitogen-activated protein kinases (MAPKs) belong to the group of serine–threonine kinases that are rapidly activated in response to growth factor stimulation. In adult mammalian cells, the MAPK family includes extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2 or p44mapk and p42mapk), which translocate to the nucleus and integrate signals from second messengers leading to cellular proliferation or differentiation, but the specific role of MAPKs in neonatal pulmonary vascular smooth muscle is not well understood. Expression of p44mapk and p42mapk in primary cultured pulmonary vascular smooth muscle cells from neonatal (1–2 day old) rats was identified by Western immunoblot analysis and treatment with 10 nM endothelin-1 (ET-1), a potent vasoconstrictor with vascular mitogenic properties, induced cell proliferation, and phosphorylation of both p44mapk and p42mapk. The protein kinase C (PKC) isozyme inhibitor (α, β, γ, δ, ζ) Go 6983, the ETA receptor antagonist BQ 123, and the MAPK kinase inhibitor PD98059 blocked the cell proliferation response to ET-1. Also, BQ 123, Go 6983, and PKC inhibitor 20-28 (Myr-N-FARKGAL-RQ-NH2-PKCα antagonist) inhibited ET-1–induced phosphorylation of both p44mapk and p42mapk. In contrast, the reactive oxygen species (ROS) inhibitor diphenylene iodonium (DPI), the PKCδ inhibitor rottlerin, and the ETB receptor antagonist BQ 788 did not block ET-1–induced phosphorylation of MAPKs. Collectively, these data demonstrate the expression and phosphorylation of MAPKs by ET-1 and suggests that MAPK activation and cell proliferation by ET-1 occurs via ETA receptor stimulation and specific PKC isozyme activation in rat neonatal pulmonary vascular smooth muscle.

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Acknowledgements

The authors gratefully acknowledge the technical assistance of Louise Meadows and Heather Redd. This work was supported by a Research Grant award (6-FY01-289) from the March of Dimes Birth Defect Foundation (S.A. Barman), and National Institutes of Health Grants HL-68026 (S.A. Barman), HL-58139 (M.B. Marrero), and DK50268 (M.B. Marrero), and an American Heart Association Established Investigator Award (M.B. Marrero).

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  1. Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia, 30912, USA

    Scott A. Barman

  2. Vascular Biology Center, Medical College of Georgia, Augusta, Georgia, 30912, USA

    Mario B. Marrero

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  2. Mario B. Marrero
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Correspondence to Scott A. Barman.

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Barman, S.A., Marrero, M.B. Mechanism of Endothelin-1 Activation of Map Kinases in Neonatal Pulmonary Vascular Smooth Muscle. Lung 183, 425–439 (2005). https://doi.org/10.1007/s00408-005-2554-3

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