Regulation of MAP kinase-mediated endothelial dysfunction in hyperglycemia via arginase I and eNOS dysregulation

Safoura Mazrouei, Fatemeh Sharifpanah, Robert William Caldwell, Marcus Franz, Alia Shatanawi, Johanna Muessig, Michael Fritzenwanger, P. Christian Schulze, Christian Jung

Research output: Contribution to journalArticle

Abstract

Emerging evidence suggests that arginase contributes to endothelial dysfunction in diabetes. Intracellular signaling pathways, which interplay between arginase and eNOS enzyme activity leading to the development of endothelial dysfunction in hyperglycemia are not fully understood. Here, we analyzed the possible involvement of hyperglycemia (HG) induced arginase expression in eNOS protein regulation and activity and also the impact of arginase inhibition on eNOS activity. Furthermore, the roles of p38 MAPK and Erk1/2 phosphorylation in upregulation of arginase expression and eNOS dysregulation in endothelial cells (ECs) under hyperglycemia were evaluated. Protein analysis showed a concurrent increase in arginase I expression and decrease in eNOS expression and phosphorylation at Ser1177 under HG conditions. There was no simultaneous change in phosphorylation of eNOS at Thr495 in HG. Arginase inhibition prevented increased arginase activity, restored impaired NO bioavailability and reduced superoxide anion generation. Inhibition of MAP-kinases demonstrated that, unlike Erk1/2, p38 MAPK is an upstream activator in a signaling cascade leading to increased arginase I in HG conditions. P38 MAPK protein expression and phosphorylation were increased in response to HG. In the presence of a p38 MAPK inhibitor, HG-induced arginase expression was blunted. Although Erk1/2 was activated in HG, increased arginase expression was not blocked by co-treatment with an Erk1/2 inhibitor. Activation of both, p38 MAPK and Erk1/2 in HG, induced a downregulation in eNOS activity. Hence, applying MAPK inhibitors increased eNOS phosphorylation in HG. In conclusion, these findings demonstrate contributions of arginase I in the development of endothelial cell dysfunction under HG conditions via impaired eNOS regulation, which maybe mediated by p38 MAPK.

Original languageEnglish (US)
Pages (from-to)1398-1411
Number of pages14
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1866
Issue number9
DOIs
StatePublished - Sep 1 2019

Fingerprint

Arginase
Hyperglycemia
Phosphotransferases
p38 Mitogen-Activated Protein Kinases
Phosphorylation
Endothelial Cells
Proteins
Superoxides
Biological Availability
Up-Regulation
Down-Regulation

Keywords

  • Arginase
  • Endothelial nitric oxide synthase (eNOS)
  • Hyperglycemia (HG)
  • L-arginine
  • MAPK
  • Superoxide anion (O )

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Regulation of MAP kinase-mediated endothelial dysfunction in hyperglycemia via arginase I and eNOS dysregulation. / Mazrouei, Safoura; Sharifpanah, Fatemeh; Caldwell, Robert William; Franz, Marcus; Shatanawi, Alia; Muessig, Johanna; Fritzenwanger, Michael; Schulze, P. Christian; Jung, Christian.

In: Biochimica et Biophysica Acta - Molecular Cell Research, Vol. 1866, No. 9, 01.09.2019, p. 1398-1411.

Research output: Contribution to journalArticle

Mazrouei, S, Sharifpanah, F, Caldwell, RW, Franz, M, Shatanawi, A, Muessig, J, Fritzenwanger, M, Schulze, PC & Jung, C 2019, 'Regulation of MAP kinase-mediated endothelial dysfunction in hyperglycemia via arginase I and eNOS dysregulation', Biochimica et Biophysica Acta - Molecular Cell Research, vol. 1866, no. 9, pp. 1398-1411. https://doi.org/10.1016/j.bbamcr.2019.05.004
Mazrouei, Safoura ; Sharifpanah, Fatemeh ; Caldwell, Robert William ; Franz, Marcus ; Shatanawi, Alia ; Muessig, Johanna ; Fritzenwanger, Michael ; Schulze, P. Christian ; Jung, Christian. / Regulation of MAP kinase-mediated endothelial dysfunction in hyperglycemia via arginase I and eNOS dysregulation. In: Biochimica et Biophysica Acta - Molecular Cell Research. 2019 ; Vol. 1866, No. 9. pp. 1398-1411.
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AU - Caldwell, Robert William

AU - Franz, Marcus

AU - Shatanawi, Alia

AU - Muessig, Johanna

AU - Fritzenwanger, Michael

AU - Schulze, P. Christian

AU - Jung, Christian

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KW - Arginase

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KW - L-arginine

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