Endothelial pyruvate kinase M2 maintains vascular integrity
Boa Kim, Cholsoon Jang, Harita Dharaneeswaran, Jian Li, Mohit Bhide, Steven Yang, Kristina Li, Zolt Arany
Boa Kim, Cholsoon Jang, Harita Dharaneeswaran, Jian Li, Mohit Bhide, Steven Yang, Kristina Li, Zolt Arany
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Research Article Metabolism Vascular biology

Endothelial pyruvate kinase M2 maintains vascular integrity

Abstract

The M2 isoform of pyruvate kinase (PKM2) is highly expressed in most cancer cells, and has been studied extensively as a driver of oncogenic metabolism. In contrast, the role of PKM2 in nontransformed cells is little studied, and nearly nothing is known of its role, if any, in quiescent cells. We show here that endothelial cells express PKM2 almost exclusively over PKM1. In proliferating endothelial cells, PKM2 is required to suppress p53 and maintain cell cycle progression. In sharp contrast, PKM2 has a strikingly different role in quiescent endothelial cells, where inhibition of PKM2 leads to degeneration of tight junctions and barrier function. Mechanistically, PKM2 regulates barrier function independently of its canonical activity as a pyruvate kinase. Instead, PKM2 suppresses NF-kB and its downstream target, the vascular permeability factor angiopoietin 2. As a consequence, loss of endothelial cell PKM2 in vivo predisposes mice to VEGF-induced vascular leak, and to severe bacteremia and death in response to sepsis. Together, these data demonstrate new roles of PKM2 in quiescent cells, and highlight the need for caution in developing cancer therapies that target PKM2.

Authors

Boa Kim, Cholsoon Jang, Harita Dharaneeswaran, Jian Li, Mohit Bhide, Steven Yang, Kristina Li, Zolt Arany

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Figure 9

Deletion of endothelial PKM2 exacerbates sepsis-induced responses and mortality in CLP model.

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Deletion of endothelial PKM2 exacerbates sepsis-induced responses and mo...
(A) Lung edema was measured as the ratio of the wet weight to the dry weight of the left lobe 20 hours after sham or CLP surgery. Each group used 12- to 14-week-old mice (n = 8 each group). (B) PKM2ΔEC mice have higher bacteremia before and after CLP. Each group used 20- to 22-week-old mice. Representative images of bacterial growth on blood agar and quantification of number of bacterial CFUs in blood (n = 8 each group) are shown. (C) Survival rates of WT and PKM2ΔEC mice after CLP surgery. Each group used 20- to 22-week-old mice (n = 8 each group). (D) Representative immunohistochemistry images of NF-kB RELA subunit (red) 20 hours after sham or CLP surgery. Mice 12- to 14-weeks-old were used. Scale bar, 100 μm. (E) Representative immunohistochemistry images of macrophages (F4/80 in red), endothelial cells (IB4 in green), and nucleus (DAPI in blue). Each group used 12- to 14-week-old mice (n = 12 each group). Scale bar, 50 μm. (F) Plasma levels of ANGPT2 before and after CLP as determined by ELISA analysis. Each group used 12- to 14-week-old mice (n = 12 each group). (G) Survival rates of PKM2ΔEC mice with IgG or ABTAA injection after CLP. Each group used 8- to 10-week-old mice (n = 8 each group). (H) Rescued bacteremia by ABTAA administration in PKM2ΔEC mice after CLP. Representative images of bacterial growth on blood agar. Quantification of number of bacterial CFUs in blood. Each group used 8- to 10-week-old mice (n = 8 each group). All data are mean ± SD. *P < 0.05, **P < 0.01, by 2-tailed Student’s t test.