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Kruppel‐Like Factor 15: A Critical Transcriptional Regulator Of Hypoxia Induced Endothelial Arginase 2
Author(s) -
Pandey Deepesh,
Hori Daijiro,
Santhanam Lakshmi,
Berkowitz Dan,
Romer Lewis
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.719.10
Subject(s) - hypoxia (environmental) , chromatin immunoprecipitation , regulator , endothelium , endothelial dysfunction , downregulation and upregulation , transcription factor , biology , hypoxia inducible factors , microbiology and biotechnology , cancer research , immunology , endocrinology , chemistry , gene expression , biochemistry , promoter , gene , oxygen , organic chemistry
Objective Kruppel Like Factor 15 has recently been shown to be critical for activation of proinflammatory processes in vascular smooth muscle and atherogenesis. Although KLF15 is abundantly expressed in vascular endothelium there is a significant lack of knowledge regarding the role of KLF15 in the regulation of vascular endothelial function. Here we tested the hypothesis that a KLF15 is a critical regulator of Arg2 transcription in response to hypoxia. Approach and Results Adenovirally mediated overexpression of KLF15 in human pulmonary microvascular endothelial cells (HPMEC) and in rat pulmonary arteries decreased Arg2 mRNA, protein, and activity. HPMECs exposed to 48 hours of hypoxia exhibited a robust increase in Arg2 protein and mRNA expression and a reciprocal decrease in KLF15 protein levels that remain sustained after 24 hours of reoxygenation. Further, decreased KLF15 protein levels observed in hypoxia exposed HPMEC occurs through augmented conjugation of Ubiquitin to KLF15 that results in enhanced clearance of KLF15 via proteasomal degradation. Chromatin immunoprecipitation indicated direct binding of KLF15 to the Arg2 promoter, which was relieved when HPMEC were exposed to hypoxia, Finally, overexpression of KLF15 reversed hypoxia‐induced augmentation of arginase activity and decrements in Nitric Oxide production in HPMEC, and also reversed hypoxia‐induced endothelial dysfunction in isolated mice aortic and rat pulmonary artery rings were. Conclusions KLF15 is a critical regulator and repressor of endothelial Arg2 expression, and thereby, NO and pulmonary endothelial function. Overexpression or activation of KLF15 may represent novel therapeutic strategies for pulmonary hypertension. Support or Funding Information NIH R01‐HL089668 NIH R01‐HL124213 American Heart Association Postdoctoral Fellow Award from American Heart Association (13POST16810011) to D. Pandey