The alterations of gene expression in aorta from endothelial nitric oxide synthase (eNOS)-deficient mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE123855 | GEO | 2018/12/15
REPOSITORIES: GEO
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Project description:The alterations of gene expression in aorta from endothelial nitric oxide synthase (eNOS)-deficient mice
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Project description:Chen2006 - Nitric Oxide Release from
Endothelial Cells
This model is described in the article:
Theoretical analysis of
biochemical pathways of nitric oxide release from vascular
endothelial cells.
Chen K, Popel AS.
Free Radic. Biol. Med. 2006 Aug; 41(4):
668-680
Abstract:
Vascular endothelium expressing endothelial nitric oxide
synthase (eNOS) produces nitric oxide (NO), which has a number
of important physiological functions in the microvasculature.
The rate of NO production by the endothelium is a critical
determinant of NO distribution in the vascular wall. We have
analyzed the biochemical pathways of NO synthesis and
formulated a model to estimate NO production by the
microvascular endothelium under physiological conditions. The
model quantifies the NO produced by eNOS based on the kinetics
of NO synthesis and the availability of eNOS and its
intracellular substrates. The predicted NO production from
microvessels was in the range of 0.005-0.1 microM/s. This range
of predicted values is in agreement with some experimental
values but is much lower than other rates previously measured
or estimated from experimental data with the help of
mathematical modeling. Paradoxical discrepancies between the
model predictions and previously reported results based on
experimental measurements of NO concentration in the vicinity
of the arteriolar wall suggest that NO can also be released
through eNOS-independent mechanisms, such as catalysis by
neuronal NOS (nNOS). We also used our model to test the
sensitivity of NO production to substrate availability, eNOS
concentration, and potential rate-limiting factors. The results
indicated that the predicted low level of NO production can be
attributed primarily to a low expression of eNOS in the
microvascular endothelial cells.
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Project description:Endothelial nitric oxide synthase (eNOS) catalyzes the conversion of L-arginine and molecular oxygen into L-citrulline and nitric oxide (NO), a gaseous second messenger that influences cardiovascular physiology and disease. Several mechanisms regulate eNOS activity and function, including phosphorylation at Ser and Thr residues and protein-protein interactions. Combining a tandem affinity purification approach and mass spectrometry, we identified stromal cell-derived factor 2 (SDF2) as a component of the eNOS macromolecular complex in endothelial cells. SDF2 knockdown impaired agonist stimulated NO synthesis and decreased phosphorylation of eNOS at Ser1177, a key event required for maximal activation of eNOS. Conversely, SDF2 overexpression dose-dependently increased NO synthesis through a mechanism involving Akt and calcium (induced with ionomycin), which increased the phosphorylation of Ser1177 in eNOS. NO synthesis by iNOS (inducible NOS) and nNOS (neuronal NOS) was also enhanced upon SDF2 overexpression. We found that SDF2 was a client protein of the chaperone protein Hsp90, interacting preferentially with the M domain of Hsp90, which is the same domain that binds to eNOS. In endothelial cells exposed to vascular endothelial growth factor (VEGF), SDF2 was required for the binding of Hsp90 and calmodulin to eNOS, resulting in eNOS phosphorylation and activation. Thus, our data describe a function for SDF2 as a component of the Hsp90-eNOS complex that is critical for signal transduction in endothelial cells.
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Project description:Nitric oxide (NO) is a crucial gaseous signaling molecule engaged in a variety of physiological and pathological processes. It is produced by three isoenzymes called nitric oxide synthases (NOS): neuronal, inducible and endothelial NOS (eNOS). eNOS-derived NO plays an important role in endothelium-dependent vasodilation as well as in lipid and glucose homeostasis in the liver. In addition, it has been shown that NO exert a beneficial effect on mitochondrial biogenesis and respiration. Thus, the aim of our study was to used iTRAQ-based quantitative proteomics to investigate the changes in protein expression in the mitochondrial and cytosolic fractions isolated from the liver of the double (apolipoprotein E (apoE) and eNOS) knockout (apoE/eNOS-DKO) mice as compared to apoE-/- mice – an animal model of atherosclerosis and hepatic steatosis. Collectively, our proteomic approach revealed the increased expression of proteins related to gluconeogenesis, fatty acids and cholesterol biosynthesis as well as the decreased expression of proteins participated in triglyceride breakdown, cholesterol transport, protein transcription & translation and processing in endoplasmic reticulum (ER). Moreover, one of the most down-regulated proteins were major urinary proteins (MUPs), which are abundantly expressed in the liver and are involved in the regulation of lipid and glucose metabolism as well as mitochondrial function. However, the exact functional consequences of the revealed alterations require further investigation.
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Project description:Soon after release from stemness, a relevant portion of mouse embryonic stem cells (mES), kept in naïve state by MEK inhibitor, GSK3 inhibitor and LIF (2i/L), expresses endothelial nitric oxide synthase (eNOS) and endogenously synthesizes nitric oxide (NO). In this condition, an eNOS/NO-positive subpopulation (ESNO+) has been recognized by 4-amino-5-methylamino-2′,7′-difluorescein (DAF) fluorescence. Sorted ESNO+ cells expressed high levels of mesendodermal markers and efficiently generated cardiovascular precursors compared to eNOS/NO-negative cells (ESNO-). Mechanistically, the endogenous NO production deter- mined a rapid S-nitrosylation of Hdac2, a post-translational modification that compromised Hdac2 association with the transcription repression factor Zeb1. This condition destabilized Zeb1/chromatin interaction with genomic loci encoding for mesendodermal genes. Remarkably, Zeb1 or Hdac2 targeting activated an unscheduled transcription of mesendodermal lineage-associated genes in naïve mES revealing the Hdac2-Zeb1 pathway important for stemness maintenance in 2i/L. In contrast, eNOS targeting significantly reduced the endogenous NO production preventing the activation of mesendodermal gene transcription.
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