Endothelial nitric oxide synthase (eNOS) variants in cardiovascular disease: pharmacogenomic implications.
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ABSTRACT:
SUBMITTER: Bhanoori M
PROVIDER: S-EPMC3121274 | biostudies-literature | 2011 May
REPOSITORIES: biostudies-literature
Publications
Endothelial nitric oxide synthase (eNOS) variants in cardiovascular disease: pharmacogenomic implications.
The Indian journal of medical research 20110501
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Project description:The Global Burden of Disease Study identified cardiovascular risk factors as leading causes of global deaths and life years lost. Endothelial dysfunction represents a pathomechanism that is associated with most of these risk factors and stressors, and represents an early (subclinical) marker/predictor of atherosclerosis. Oxidative stress is a trigger of endothelial dysfunction and it is a hall-mark of cardiovascular diseases and of the risk factors/stressors that are responsible for their initiation. Endothelial function is largely based on endothelial nitric oxide synthase (eNOS) function and activity. Likewise, oxidative stress can lead to the loss of eNOS activity or even "uncoupling" of the enzyme by adverse regulation of well-defined "redox switches" in eNOS itself or up-/down-stream signaling molecules. Of note, not only eNOS function and activity in the endothelium are essential for vascular integrity and homeostasis, but also eNOS in perivascular adipose tissue plays an important role for these processes. Accordingly, eNOS protein represents an attractive therapeutic target that, so far, was not pharmacologically exploited. With our present work, we want to provide an overview on recent advances and future therapeutic strategies that could be used to target eNOS activity and function in cardiovascular (and other) diseases, including life style changes and epigenetic modulations. We highlight the redox-regulatory mechanisms in eNOS function and up- and down-stream signaling pathways (e.g., tetrahydrobiopterin metabolism and soluble guanylyl cyclase/cGMP pathway) and their potential pharmacological exploitation.
| S-EPMC6337296 | biostudies-literature
Project description:Preeclampsia (PE) is a common pregnancy-related hypertensive disorder and is a leading cause of maternal and perinatal morbidity and mortality. The incidence of PE and its associated health care costs have been increasing in the United States over the past three decades. Pregnancies complicated by PE put both the mother and child at increased risk for chronic illnesses such as cardiovascular disease, cerebrovascular disease, and cognitive impairment later in life. To date, there is no effective treatment for PE and the etiology of PE is largely unknown. While human epidemiological studies have established an association between various genetic factors and PE, a causative link between genes associated with PE and PE development has been difficult to establish. Human studies have shown that variants in eNOS (endothelial nitric oxide synthase, also known as NOS3) gene are associated with PE, and animal experimental studies have provided evidence to show the potential functional connection between the eNOS gene and PE. Here we review several studies that investigated the role of eNOS in PE, as well as studies that described how manipulating the eNOS/NO pathway could aid in disease intervention.
| S-EPMC10929736 | biostudies-literature
Project description:Endothelial NOS (eNOS)-derived NO is a key factor in regulating microvascular permeability. We demonstrated previously that eNOS translocation from the plasma membrane to the cytosol is required for hyperpermeability. Herein, we tested the hypothesis that eNOS activation in the cytosol is necessary for agonist-induced hyperpermeability. To study the fundamental properties of endothelial cell monolayer permeability, we generated ECV-304 cells that stably express cDNA constructs targeting eNOS to the cytosol or plasma membrane. eNOS-transfected ECV-304 cells recapitulate the eNOS translocation and permeability properties of postcapillary venular endothelial cells (Sánchez, F. A., Rana, R., Kim, D. D., Iwahashi, T., Zheng, R., Lal, B. K., Gordon, D. M., Meininger, C. J., and Durán, W. N. (2009) Proc. Natl. Acad. Sci. U.S.A. 106, 6849-6853). We used platelet-activating factor (PAF) as a proinflammatory agonist. PAF activated eNOS by increasing phosphorylation of Ser-1177 and inducing dephosphorylation of Thr-495, increasing NO production, and elevating permeability to FITC-dextran 70 in monolayers of cells expressing wild-type and cytosolic eNOS. PAF failed to increase permeability to FITC-dextran 70 in monolayers of cells transfected with eNOS targeted to the plasma membrane. Interestingly, this occurred despite eNOS Ser-1177 phosphorylation and production of comparable amounts of NO. Our results demonstrate that the presence of eNOS in the cytosol is necessary for PAF-induced hyperpermeability. Our data provide new insights into the dynamics of eNOS and eNOS-derived NO in the process of inflammation.
| S-EPMC3162400 | biostudies-literature
Project description:Nitric oxide (NO) is highly reactive, produced in endothelial cells by endothelial NO synthase (eNOS) and has been implicated in sickle cell pathophysiology. We evaluated the distribution of functionally significant eNOS variants (the T786C variant in the promoter region, the Glu298Asp variant in exon 7, and the variable number of tandem repeats (VNTR) in intron 4) in Africans, African Americans and Caucasians. The C-786 variant was more common in Caucasians than in Africans and African Americans. Consistent with other findings, the Asp-298 variant had the highest frequency in Caucasians followed by African Americans, but was completely absent in Africans. The very rare intron 4 allele, eNOS 4c, was found in some Africans and African Americans, but not in Caucasians. eNOS 4d allele was present in 2 Africans. These findings suggest a consistent and widespread genomic diversity in the distribution of eNOS variants in Africans, comparative to African Americans and Caucasians.
| S-EPMC3562081 | biostudies-other
Project description:Endothelial dysfunction leads to lethal vascular complications in diabetes and related metabolic disorders. Here, we demonstrate that de novo lipogenesis, an insulin-dependent process driven by the multifunctional enzyme fatty-acid synthase (FAS), maintains endothelial function by targeting endothelial nitric-oxide synthase (eNOS) to the plasma membrane. In mice with endothelial inactivation of FAS (FASTie mice), eNOS membrane content and activity were decreased. eNOS and FAS were physically associated; eNOS palmitoylation was decreased in FAS-deficient cells, and incorporation of labeled carbon into eNOS-associated palmitate was FAS-dependent. FASTie mice manifested a proinflammatory state reflected as increases in vascular permeability, endothelial inflammatory markers, leukocyte migration, and susceptibility to LPS-induced death that was reversed with an NO donor. FAS-deficient endothelial cells showed deficient migratory capacity, and angiogenesis was decreased in FASTie mice subjected to hindlimb ischemia. Insulin induced FAS in endothelial cells freshly isolated from humans, and eNOS palmitoylation was decreased in mice with insulin-deficient or insulin-resistant diabetes. Thus, disrupting eNOS bioavailability through impaired lipogenesis identifies a novel mechanism coordinating nutritional status and tissue repair that may contribute to diabetic vascular disease.
| S-EPMC3024788 | biostudies-literature
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
Project description:A variety of studies have suggested that the 4b/a polymorphism in the endothelial nitric oxide synthase (eNOS) was associated with coronary artery disease (CAD) risk. However, the data remain conflicting. The aim of the present meta-analysis was to estimate the overall association between risk of CAD and eNOS 4b/a polymorphism. Case-control, cohort or cross-sectional studies evaluating the association between eNOS 4b/a polymorphism and CAD susceptibility were systematically identified in PubMed up to 31 October 2013. Pooled odds ratios (OR) and corresponding 95% confidence intervals (CIs) were calculated to assess the association in overall and subgroup analyses. A total of 10,617 cases and 8302 controls from 37 studies were included in the study. The results of overall analysis revealed significant positive associations between CAD risk and eNOS 4b/a polymorphism in homozygote comparisons (OR = 1.47, 95% CI = 1.16-1.87), heterozygote comparisons (OR = 1.14, 95% CI = 1.02-1.27) and dominant models (OR = 1.18, 95% CI = 1.06-1.33). In subgroup analyses, similar associations were identified in African individuals, as determined using population-based source subgroups and noted in small-and-moderate sample size subgroups (case sample size or control sample size <500). The current meta-analysis revealed that eNOS 4b/a polymorphisms could be a risk factor for developing CAD, particularly in African populations and population-based subgroups.
| S-EPMC4057714 | biostudies-literature
Project description:BackgroundPreeclampsia (PE) is a complex pregnancy hypertensive disorder with multifaceted etiology. The endothelial nitric oxide synthase (eNOS) gene and nitric oxide (NO) levels has been reported to be associated with PE predisposition in various populations. Therefore, present study was designed to investigate the role of NO levels and eNOS gene variants in preeclamptic women in Pakistan.MethodsA total of 600 women were evaluated, 188 of PE with mild features, 112 of PE with severe features and 300 normotensive pregnant women. NO levels were detected by Greiss reaction method and genotyping following sequencing was conducted for eNOS gene variants. Further insilico studies were performed to get insights into the structural and functional impact of identifies mutation on eNOS protein as well as on protein regulation.ResultsReduced concentrations of NO were reported in all PE groups (p < 0.05) as compared to controls. The frequency of c.894 T (p.298Asp) and g.-786C alleles were significantly associated with PE. In addition, novel homozygous variant g.2051G > A was also significantly associated with PE when compared to normotensive women. Dynamic simulation studies revealed that Glu298Asp mutation destabilize the protein molecule and decrease the overall stability of eNOS protein. Molecular docking analysis of mutant promoter with transcription factors STAT3 and STAT6 proposed changes in protein regulation upon these reported mutations in upstream region of the gene.ConclusionConsidering the results of current study, the functional alterations induced by these variants may influence the bioavailability of NO and represents a genetic risk factor for increased susceptibility to PE. However, large studies or meta-analysis are necessary to validate these findings.
| S-EPMC8320179 | biostudies-literature
Project description:EGFR mutation of Non-small cell lung cancers (NSCLC) was predominantly seen in Asian population and it was considered as a predictor of responsiveness. Eendothelial nitric oxide synthase (eNOS) plays a vital role in chronic inflammation and carcinogenesis. In this study, we aimed to explore the association between the genetic polymorphisms of eNOS (-786T/C and 894 G/T) and EGFR mutation in patients with lung adenocarcinoma. A total of 277 patients with diagnosed lung adenocarcinoma were recruited between years 2012 and 2015. All study subjects underwent the analysis of eNOS genetic variants (-786 T/C and 894 G/T) using real-time polymerase chain reaction (PCR) genotyping. Our results showed that, among the 277 patients, variant types (GT + TT) of eNOS 894 G/T polymorphism were significantly positively correlated with EGFR mutation type, specifically exon 19 in-frame deletion. With the subgroup of EGFR L858R mutation, variant genotypes (GT + TT) of eNOS 894 G/T were significantly associated with lymph node invasion. Moreover, in silico analysis indicated that eNOS 894 G/T altered the eNOS expression. In conclusion, our study showed that eNOS 894 G/T variants were significantly associated with EGFR mutation types of lung adenocarcinoma, specifically exon 19 in-frame deletion. This may be utilized as a prediction of tumor invasiveness and therapy responsiveness.
| S-EPMC6036879 | biostudies-literature
Project description:Phytoestrogens are plant-derived chemicals that are found in many foods and have estrogenic activity. We previously showed that blackcurrant extract (BCE) and anthocyanins have phytoestrogenic activity mediated via estrogen receptors (ERs), and anthocyanins may improve vascular function. BCE contains high levels of anthocyanins, but their health-promoting effects are unclear. This study examined the effects of BCE on the regulation of endothelial nitric oxide synthase (eNOS) expression and nitric oxide (NO) synthesis in human endothelial cells as key regulators in cardiovascular disease. The results showed that eNOS mRNA levels were significantly upregulated in BCE- or anthocyanin-treated human vascular endothelial cells but decreased in cells treated with fulvestrant, an ER antagonist. These results corresponded with NO levels, suggesting that BCE and anthocyanin may regulate NO synthesis via eNOS expression. Thus, the phytoestrogenic effects exerted by BCE via ERs influenced eNOS mRNA expression and NO synthesis. In vivo, we investigated whether anthocyanin-rich BCE upregulated eNOS protein expression in ovariectomized (OVX) rats, a widely used animal model of menopause. Our results showed that anthocyanin-rich BCE significantly upregulated eNOS mRNA levels and NO synthesis through phytoestrogenic activity and therefore promoted blood vessel health in OVX rats as a postmenopausal model.
| S-EPMC6480453 | biostudies-literature