Identification of activators of erk5 transcriptional activity by high-throughput screening and the role of endothelial ERK5 in vasoprotective effects induced by statins and antimalarial agents

Nhat Tu Le, Yuichiro Takei, Yuki Izawa-Ishizawa, Kyungsun Heo, Hakjoo Lee, Alan V. Smrcka, Benjamin L. Miller, Kyung Ae Ko, Sara Ture, Craig Morrell, Keigi Fujiwara, Masashi Akaike, Jun-ichi Abe

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Because ERK5 inhibits endothelial inflammation and dysfunction, activating ERK5 might be a novel approach to protecting vascular endothelial cells (ECs) against various pathological conditions of the blood vessel. We have identified small molecules that protect ECs via ERK5 activation and determined their contribution to preventing cardiac allograft rejection. Using highthroughput screening, we identified certain statins and antimalarial agents including chloroquine, hydroxychloroquine, and quinacrine as strong ERK5 activators. Pitavastatin enhanced ERK5 transcriptional activity and Kruppel-like factor-2 expression in cultured human and bovine ECs, but these effects were abolished by the depletion of ERK5. Chloroquine and hydroxychloroquine upregulated ERK5 kinase activity and inhibited VCAM-1 expression in an ERK5-dependent but MAPK/ERK kinase 5- and Kruppel-like factor 2/4-independent manner. Leukocyte rolling and vascular reactivity were used to evaluate endothelial function in vivo, and we found that EC-specific ERK5 knockout (ERK5-EKO) mice exhibited increased leukocyte rolling and impaired vascular reactivity, which could not be corrected by pitavastatin. The role of endothelial ERK5 in acute cardiac allograft rejection was also examined by heterotopic grafting of the heart obtained from either wild-type or ERK5-EKO mice into allomismatched recipient mice. A robust increase in both inflammatory gene expression and CD45-positive cell infiltration into the graft was observed. These tissue rejection responses were inhibited by pitavastatin in wild-type but not ERK5-EKO hearts. Our study has identified statins and antimalarial drugs as strong ERK5 activators and shown that ERK5 activation is preventive of endothelial inflammation and dysfunction and acute allograft rejection.

Original languageEnglish (US)
Pages (from-to)3803-3815
Number of pages13
JournalJournal of Immunology
Volume193
Issue number7
DOIs
StatePublished - Oct 1 2014

Fingerprint

Hydroxymethylglutaryl-CoA Reductase Inhibitors
Antimalarials
Endothelial Cells
Leukocyte Rolling
Hydroxychloroquine
Allografts
Blood Vessels
Chloroquine
MAP Kinase Kinase 5
Mitogen-Activated Protein Kinase 7
Kruppel-Like Transcription Factors
Inflammation
Quinacrine
Vascular Cell Adhesion Molecule-1
Heart Transplantation
Transplants
Gene Expression
pitavastatin

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Identification of activators of erk5 transcriptional activity by high-throughput screening and the role of endothelial ERK5 in vasoprotective effects induced by statins and antimalarial agents. / Le, Nhat Tu; Takei, Yuichiro; Izawa-Ishizawa, Yuki; Heo, Kyungsun; Lee, Hakjoo; Smrcka, Alan V.; Miller, Benjamin L.; Ko, Kyung Ae; Ture, Sara; Morrell, Craig; Fujiwara, Keigi; Akaike, Masashi; Abe, Jun-ichi.

In: Journal of Immunology, Vol. 193, No. 7, 01.10.2014, p. 3803-3815.

Research output: Contribution to journalArticle

Le, Nhat Tu ; Takei, Yuichiro ; Izawa-Ishizawa, Yuki ; Heo, Kyungsun ; Lee, Hakjoo ; Smrcka, Alan V. ; Miller, Benjamin L. ; Ko, Kyung Ae ; Ture, Sara ; Morrell, Craig ; Fujiwara, Keigi ; Akaike, Masashi ; Abe, Jun-ichi. / Identification of activators of erk5 transcriptional activity by high-throughput screening and the role of endothelial ERK5 in vasoprotective effects induced by statins and antimalarial agents. In: Journal of Immunology. 2014 ; Vol. 193, No. 7. pp. 3803-3815.
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AU - Izawa-Ishizawa, Yuki

AU - Heo, Kyungsun

AU - Lee, Hakjoo

AU - Smrcka, Alan V.

AU - Miller, Benjamin L.

AU - Ko, Kyung Ae

AU - Ture, Sara

AU - Morrell, Craig

AU - Fujiwara, Keigi

AU - Akaike, Masashi

AU - Abe, Jun-ichi

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