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Gene expression profiling of human brain microvascular endothelial cells with Nox4 overexpression

ABSTRACT: The objective of the present study is to investigate the effect of Nox4 overexpression on human brain endothelial cells. Comparative gene expression analysis was performed using cultured human brain microvascular endothelial cells with adenovirus-mediated LacZ or Nox4 overexpression. Gene expression was analyzed using 3D-Gene® Human 25k oligonucleotide microarrays and computational gene expression analysis tools. Nox4 overexpression resulted in significant changes in numerous genes related with (1) signaling pathways mediated by cytokines and chemokines, (2) stress responses, such as NFB activation, and (3) leukocyte chemotaxis and migration.

ORGANISM(S): Homo sapiens

PROVIDER: GSE205176 | GEO | 2023/06/01

REPOSITORIES: GEO

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Project description:ABSTRACT Rationale Premature senescence is conducive to aging and cardiovascular diseases. Nrf2 transcription factor, the master orchestrator of adoptive response to cellular stress, has been implicated in regulation of premature senescence in fibroblasts, neural and mesenchymal stem cells by transactivation of antioxidant gene expression. However, as we show here, human primary endothelial cells (ECs) devoid of Nrf2 and murine Nrf2 transcriptional knockout (tKO) aortas are senescent but do not encounter oxidative stress and damage, what contradicts this mechanism. Moreover, a molecular switch between normal, senescent and apoptotic fate remains unknown. Objective To elucidate the mechanism of Nrf2-related premature senescence of vascular system, to understand why Nrf2 deregulation does not cause oxidative stress exclusionary in ECs and to indicate a molecular switch determining ECs fate. Methods and Results Herein we evidence that ECs deficient in Nrf2 protein, or with limited Nrf2 activity in shear stress conditions, exhibit excessive S-nitrosylation of proteins. It is also a characteristic of Nrf2 tKO murine aortas, as determined by biotin switch assay in situ. Mass spectrometry analysis reveals that NOX4 is S-nitrosylated exclusively in ECs devoid of Nrf2. A functional role of S-nitrosylation is protection of ECs from death by inhibition of NOX4-mediated oxidative damage. As a result Nrf2-deficient ECs preserve oxidative balance but are redirected to premature senescence. The same phenotype is seen in Nrf2 tKO aortas. These effects are mediated by Keap1, a direct binding partner of Nrf2 and repressor of its transcriptional activity, remaining in cytoplasm unrestrained by Nrf2. S-nitrosylation, followed by senescence, can also be triggered in smooth muscle cells (SMCs) by EC-derived paracrine induction of iNOS. Conclusions Collectively, Keap1-dependent S-nitrosylation of NOX4 hampers oxidative detriment in ECs with disturbed Nrf2 signaling and may provide defence in the adjacent aortic cells. Overabundance of unrestrained Keap1 in the cytoplasm determines fate of ECs.

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Gene expression profiling of human brain microvascular endothelial cells with Nox4 overexpression

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