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p32-Dependent p38 MAPK Activation by Arginase II Downregulation Contributes to Endothelial Nitric Oxide Synthase Activation in HUVECs

1
Department of Biological Sciences, Kangwon National University, Chuncheon, Gangwon 24341, Korea
2
Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon 24341, Korea
3
Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Gangwon 24341, Korea
*
Author to whom correspondence should be addressed.
Cells 2020, 9(2), 392; https://doi.org/10.3390/cells9020392
Received: 16 December 2019 / Revised: 26 January 2020 / Accepted: 5 February 2020 / Published: 8 February 2020
(This article belongs to the Section Cellular Pathology)
Arginase II reciprocally regulates endothelial nitric oxide synthase (eNOS) through a p32-dependent Ca2+ control. We investigated the signaling pathway of arginase II-dependent eNOS phosphorylation. Western blot analysis was applied for examining protein activation and [Ca2+]c was analyzed by microscopic and FACS analyses. Nitric oxide (NO) and reactive oxygen species (ROS) productions were measured using specific fluorescent dyes under microscopy. NO signaling pathway was tested by measuring vascular tension. Following arginase II downregulation by chemical inhibition or gene knockout (KO, ArgII−/−), increased eNOS phosphorylation at Ser1177 and decreased phosphorylation at Thr495 was depend on p38 MAPK activation, which induced by CaMKII activation through p32-dependent increase in [Ca2+]c. The protein amount of p32 negatively regulated p38 MAPK activation. p38 MAPK contributed to Akt-induced eNOS phosphorylation at Ser1177 that resulted in accelerated NO production and reduced reactive oxygen species production in aortic endothelia. In vascular tension assay, p38 MAPK inhibitor decreased acetylcholine-induced vasorelaxation responses and increased phenylephrine-dependent vasoconstrictive responses. In ApoE−/− mice fed a high cholesterol diet, arginase II inhibition restored p32/CaMKII/p38 MAPK/Akt/eNOS signaling cascade that was attenuated by p38 MAPK inhibition. Here, we demonstrated a novel signaling pathway contributing to understanding of the relationship between arginase II, endothelial dysfunction, and atherogenesis.
Keywords: arginase II; calcium; endothelial nitric oxide synthase; p38 MAPK; p32 arginase II; calcium; endothelial nitric oxide synthase; p38 MAPK; p32
MDPI and ACS Style

Koo, B.-H.; Won, M.-H.; Kim, Y.-M.; Ryoo, S. p32-Dependent p38 MAPK Activation by Arginase II Downregulation Contributes to Endothelial Nitric Oxide Synthase Activation in HUVECs. Cells 2020, 9, 392.

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