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Targeted deletion of BMK1/ERK5 in adult mice perturbs vascular integrity and leads to endothelial failure
Masaaki Hayashi, … , Richard J. Ulevitch, Jiing-Dwan Lee
Masaaki Hayashi, … , Richard J. Ulevitch, Jiing-Dwan Lee
Published April 15, 2004
Citation Information: J Clin Invest. 2004;113(8):1138-1148. https://doi.org/10.1172/JCI19890.
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Article Vascular biology Article has an altmetric score of 3

Targeted deletion of BMK1/ERK5 in adult mice perturbs vascular integrity and leads to endothelial failure

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Abstract

Big mitogen-activated protein kinase 1 (BMK1), also known as ERK5, is a member of the MAPK family. Genetic ablation of BMK1 in mice leads to embryonic lethality, precluding the exploration of pathophysiological roles of BMK1 in adult mice. We generated a BMK1 conditional mutation in mice in which disruption of the BMK1 gene is under the control of the inducible Mx1-Cre transgene. Ablation of BMK1 in adult mice led to lethality within 2–4 weeks after the induction of Cre recombinase. Physiological analysis showed that the blood vessels became abnormally leaky after deletion of the BMK1 gene. Histological analysis revealed that, after BMK1 ablation, hemorrhages occurred in multiple organs in which endothelial cells lining the blood vessels became round, irregularly aligned, and, eventually, apoptotic. In vitro removal of BMK1 protein also led to the death of endothelial cells partially due to the deregulation of transcriptional factor MEF2C, which is a direct substrate of BMK1. Additionally, endothelial-specific BMK1-KO leads to cardiovascular defects identical to that of global BMK1-KO mutants, whereas, surprisingly, mice lacking BMK1 in cardiomyocytes developed to term without any apparent defects. Taken together, the data provide direct genetic evidence that the BMK1 pathway is critical for endothelial function and for maintaining blood vessel integrity.

Authors

Masaaki Hayashi, Sung-Woo Kim, Kyoko Imanaka-Yoshida, Toshimichi Yoshida, E. Dale Abel, Brian Eliceiri, Young Yang, Richard J. Ulevitch, Jiing-Dwan Lee

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Figure 8

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BMK1-mediated MEF2C activation is required for EC survival. (A) BMK1 sti...
BMK1-mediated MEF2C activation is required for EC survival. (A) BMK1 stimulates MEF2C transactivation activity in ECs. HUVECs, MLCECs, and 293 cells were cotransfected with reporter plasmid pG5ElbLuc and GAL4-MEF2C. Additionally, control vector pcDNA3 or expression plasmids encoding MEK5(D) along with BMK1 were included in each transfection as indicated. (B and C) BMK1 mediates serum-induced MEF2C activation. MLCECs were first infected with adenovirus as indicated and were cotransfected with pG5E1bLuc and GAL4-MEF2C (B) or transfected with either pJLuc or pJSXLuc, cis-reporter plasmids of MEF2 element (C). Cells were then starved for 24 hours and stimulated with 10% serum for 6 hours before harvesting. (D) Expression of constitutively active MEF2C (MEF2C-VP16) rescued EC apoptosis caused by BMK1 deficiency. MLCECs were first infected with adenovirus as indicated and were cotransfected with GFP vector along with either control vector or MEF2C-VP16. Apoptosis in the transfected cell population (GFP-positive cells) was determined by cellular morphology 2 days after transfection. The data represent mean ± SEM of at least three independent transfections.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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