PHACTR1, a coronary artery disease risk gene, drives endothelial dysfunction
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Q Exactive
ORGANISM(S): Homo Sapiens (human)
TISSUE(S): Epithelial Cell, Cell Culture
DISEASE(S): Cardiovascular System Disease
SUBMITTER: 
Ma Xiaoxuan
LAB HEAD: Suowen Xu
PROVIDER: PXD034213 | Pride | 2022-08-16
REPOSITORIES: Pride
Similar Datasets
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.
2018-10-24 | PXD002598 | Pride
Project description:The optimal expression of endothelial nitric oxide synthase (eNOS), the hallmark of endothelial homeostasis, is vital to vascular function. Dynamically regulated by various stimuli, eNOS expression is modulated at transcriptional, post-transcriptional, and post-translational levels. However, epigenetic modulations of eNOS, particularly through long non-coding RNAs (lncRNAs) and chromatin remodeling, remain to be explored. Here we identified an enhancer-associated lncRNA that enhances eNOS expression” (LEENE). Combining RNA-sequencing and chromatin conformation capture methods, we demonstrated that LEENE is co-regulated with eNOS and that its enhancer resides in proximity to eNOS promoter in endothelial cells (ECs). Deletion of LEENE enhancer locus decreases the LEEN-eNOS proximal association and eNOS mRNA level. Inhibition of LEENE using locked nucleic acids (LNA) decreases eNOS expression and monocyte adhesion to ECs, whereas overexpression of LEENE increases eNOS expression and eNOS-derived NO in ECs. Mechanistically, LEENE facilitates the recruitment of RNA Pol II to the eNOS promoter to enhance eNOS nascent RNA transcription. Our findings unravel a new layer in eNOS regulation and provide novel insights into cardiovascular regulation involving endothelial function.
2017-10-18 | GSE103649 | GEO
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.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000676.
To cite BioModels Database, please use:
Chelliah V et al. BioModels: ten-year
anniversary. Nucl. Acids Res. 2015, 43(Database
issue):D542-8.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2018-02-20 | BIOMD0000000676 | BioModels
Project description:The SWELL1-LRRC8 complex regulates endothelial AKT-eNOS-mTOR signaling and vascular function
| PRJNA702532 | ENA
Project description:Endothelial cell (EC)-enriched protein coding genes, such as endothelial nitric oxide synthase (eNOS), define quintessential EC-specific physiologic functions. It is not clear whether long noncoding RNAs (lncRNAs) also define cardiovascular cell-type specific phenotypes, especially in the vascular endothelium. Here, we report the existence of a set of EC-enriched lncRNAs and define a role for STEEL (spliced transcript – endothelial enriched lncRNA) in angiogenic potential, macrovascular/microvascular identity and shear stress responsiveness. STEEL is expressed from the terminus of the HOXD locus and is transcribed antisense to HOXD transcription factors. STEEL RNA increases the number and integrity of de novo perfused microvessels in an in vivo model and augments angiogenesis in vitro. The STEEL RNA is polyadenylated, nuclear-enriched and has microvascular predominance. Functionally, STEEL regulates a number of genes in diverse endothelial cells. Of interest, STEEL upregulates both eNOS and the transcription factor Kruppel-like factor 2 (KLF2), and is subject to feedback inhibition by both eNOS and shear-augmented KLF2. Mechanistically, STEEL upregulation of eNOS and KLF2 is transcriptionally mediated, in part, via interaction of chromatin-associated STEEL with the poly-ADP ribosylase, PARP1. For instance, STEEL recruits PARP1 to the KLF2 promoter. This work identifies a role for EC-enriched lncRNAs in the phenotypic adaptation of ECs to both body position and hemodynamic forces, and establishes a newer role for lncRNAs in the transcriptional regulation of EC identity.
2018-02-28 | PXD008581 | Pride
Project description:The endothelial nitric oxide (NO) synthase (eNOS, or NOS3) can be activated in response to fluid shear stress and numerous agonists via cellular events such as increased intracellular Ca2+, interaction with substrate, co-factors as well as adaptor and regulatory proteins, protein phosphorylation and S-glutathionylation in addition to shuttling between distinct sub-cellular domains. While some protein interactors modulate enzymatic activity, others can be S-nitrosation targets, which are brought in close proximity to the NO source under specific conditions. The identification of proteins interacting with eNOS in human endothelial cells stimulated with serum and growth factors may provide new insight into the regulation of eNOS activity as well as NO signaling via S-nitrosation.
2021-09-08 | PXD013755 | Pride
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.
2018-03-05 | PXD006642 | Pride
Project description:MicroRNAs (miRNAs) are small non-coding RNAs that act as post-transcriptional gene modulators. Ginsenoside-Rg1, one of the active components of ginseng, has been confirmed by us as an angiogenesis inducer. Using miRNA microarray analysis, a total of 15 (including miR-214) and 3 miRNAs were found to be down- or up-regulated by Rg1 in human umbilical vein endothelial cells (HUVEC), respectively. Since miR-214 is closely related to endothelial nitric oxide synthase (eNOS) and hence angiogenesis; its expression was further validated by qRT-PCR. We also investigated the role of miR-214 on eNOS expression and in tubulogenesis of HUVEC by transfection of specific miRNA inhibitor or precursor. Our results suggested that Rg1 can down-regulate miR-214 expression in HUVEC, leading to an increase in eNOS expression which can promote angiogenesis. This result signifies a new understanding towards how a simple natural compound can affect physiological changes through modulation of miRNA expression. The study is used to investigate the role of miRNA-214 in Rg1-induced human endothelial cells.
2010-08-05 | E-GEOD-17541 | biostudies-arrayexpress
Project description:Sash1 acts as a scaffold in TLR4 signaling. We generated Sash1-/- mice, which die in the perinatal period due to respiratory distress. Constitutive or endothelial-restricted Sash1 loss leads to a reduction of surfactant-associated protein synthesis. We show that Sash1 interacts with β-arrestin 1 downstream of the TLR4 pathway to activate Akt and eNOS in microvascular endothelial cells. Generation of nitric oxide downstream of Sash1 in endothelial cells activated cGMP in adjacent alveolar type 2 cells to induce transcription of surfactant genes. Thus we identify a critical cell nonautonomous function for Sash1 in embryonic development in which endothelial Sash1 affects alveolar type 2 cells and promotes pulmonary surfactant production through nitric oxide signaling. Lack of pulmonary surfactant is a major cause of respiratory distress and mortality in preterm infants, and these findings identify the endothelium as a potential target for therapy.
2019-05-01 | GSE123889 | GEO
Project description:The dysfunction of endothelial nitric oxide synthase may be involved in development of atherosclerosis; however, the underlying molecular and cellular mechanisms of atherosclerosis are poorly understood. Here, we investigated gene expressionsin relation to atherosclerosis using endothelial nitric oxide synthase (eNOS)-deficient mice.
2018-12-15 | GSE123855 | GEO