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MEK1/2 inhibitors reverse acute vascular occlusion in mouse models of sickle cell disease.

Publication ,  Journal Article
Zhao, Y; Schwartz, EA; Palmer, GM; Zennadi, R
Published in: FASEB J
March 2016

In sickle cell disease (SCD), treatment of recurrent vasoocclusive episodes, leading to pain crises and organ damage, is still a therapeutic challenge. Vasoocclusion is caused primarily by adherence of homozygous for hemoglobin S (SS) red blood cells (SSRBCs) and leukocytes to the endothelium. We tested the therapeutic benefits of MEK1/2 inhibitors in reversing vasoocclusion in nude and humanized SCD mouse models of acute vasoocclusive episodes using intravital microscopy. Administration of 0.2, 0.3, 1, or 2 mg/kg MEK1/2 inhibitor to TNF-α-pretreated nude mice before human SSRBC infusion inhibited SSRBC adhesion in inflamed vessels, prevented the progression of vasoocclusion, and reduced SSRBC organ sequestration. By use of a more clinically relevant protocol, 0.3 or 1 mg/kg MEK1/2 inhibitor given to TNF-α-pretreated nude mice after human SSRBC infusion and onset of vasoocclusion reversed SSRBC adhesion and vasoocclusion and restored blood flow. In SCD mice, 0.025, 0.05, or 0.1 mg/kg MEK1/2 inhibitor also reversed leukocyte and erythrocyte adhesion after the inflammatory trigger of vasoocclusion and improved microcirculatory blood flow. Cell adhesion was reversed by shedding of endothelial E-selectin, P-selectin, and αvβ3 integrin, and leukocyte CD44 and β2 integrin. Thus, MEK1/2 inhibitors, by targeting the adhesive function of SSRBCs and leukocytes, could represent a valuable therapeutic intervention for acute sickle cell vasoocclusive crises.

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Published In

FASEB J

DOI

EISSN

1530-6860

Publication Date

March 2016

Volume

30

Issue

3

Start / End Page

1171 / 1186

Location

United States

Related Subject Headings

  • Vascular Diseases
  • Tumor Necrosis Factor-alpha
  • Protein Kinase Inhibitors
  • P-Selectin
  • Mice, Transgenic
  • Mice, Nude
  • Mice
  • Male
  • MAP Kinase Kinase 2
  • MAP Kinase Kinase 1
 

Citation

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MLA
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Zhao, Y., Schwartz, E. A., Palmer, G. M., & Zennadi, R. (2016). MEK1/2 inhibitors reverse acute vascular occlusion in mouse models of sickle cell disease. FASEB J, 30(3), 1171–1186. https://doi.org/10.1096/fj.15-278481
Zhao, Yulin, Evan A. Schwartz, Gregory M. Palmer, and Rahima Zennadi. “MEK1/2 inhibitors reverse acute vascular occlusion in mouse models of sickle cell disease.FASEB J 30, no. 3 (March 2016): 1171–86. https://doi.org/10.1096/fj.15-278481.
Zhao Y, Schwartz EA, Palmer GM, Zennadi R. MEK1/2 inhibitors reverse acute vascular occlusion in mouse models of sickle cell disease. FASEB J. 2016 Mar;30(3):1171–86.
Zhao, Yulin, et al. “MEK1/2 inhibitors reverse acute vascular occlusion in mouse models of sickle cell disease.FASEB J, vol. 30, no. 3, Mar. 2016, pp. 1171–86. Pubmed, doi:10.1096/fj.15-278481.
Zhao Y, Schwartz EA, Palmer GM, Zennadi R. MEK1/2 inhibitors reverse acute vascular occlusion in mouse models of sickle cell disease. FASEB J. 2016 Mar;30(3):1171–1186.

Published In

FASEB J

DOI

EISSN

1530-6860

Publication Date

March 2016

Volume

30

Issue

3

Start / End Page

1171 / 1186

Location

United States

Related Subject Headings

  • Vascular Diseases
  • Tumor Necrosis Factor-alpha
  • Protein Kinase Inhibitors
  • P-Selectin
  • Mice, Transgenic
  • Mice, Nude
  • Mice
  • Male
  • MAP Kinase Kinase 2
  • MAP Kinase Kinase 1