scholarly journals Association of the 1q25 diabetes-specific coronary heart disease locus with alterations of the γ-glutamyl cycle and increased methylglyoxal levels in endothelial cells

2020 ◽  
Author(s):  
Ada Admin ◽  
Caterina Pipino ◽  
Hetal Shah ◽  
Sabrina Prudente ◽  
Natalia Di Pietro ◽  
...  
Keyword(s):  
Coronary Heart Disease ◽  
Endothelial Cells ◽  
Heart Disease ◽  
Glutamic Acid ◽  
Risk Allele ◽  
Umbilical Vein ◽  
Glutamine Supplementation ◽  
Chd Risk ◽  
Umbilical Vein Endothelial Cells

A chromosome 1q25 variant (rs10911021) has been associated with coronary heart disease (CHD) in type 2 diabetes (T2D). In human umbilical vein endothelial cells (HUVECs), the risk allele ‘C’ is associated with lower expression of the adjacent gene <i>GLUL</i> encoding glutamine synthase, converting glutamic acid to glutamine. To further investigate the mechanisms through which this locus affects CHD risk, we measured 35 intracellular metabolites involved in glutamic acid metabolism and g-glutamyl cycle in 62 HUVEC strains carrying different rs10911021 genotypes. Eight metabolites were positively associated with the risk allele (17%-58% increase/allele copy, p=0.046-0.002), including five g-glutamyl amino acids, b-citryl-glutamate, N-acetyl-aspartyl-glutamate, and ophthalmate - a marker of g-glutamyl cycle malfunction. Consistent with these findings, the risk allele was also associated with decreased glutathione/glutamate ratio (-9%, p=0.012), decreased S-lactoylglutathione (-41%, p=0.019), and reduced detoxification of the atherogenic compound methylglyoxal (+54%, p=0.008). <i>GLUL</i> down-regulation by shRNA caused a 40% increase in methylglyoxal level, which was completely prevented by glutamine supplementation. In summary, we have identified intracellular metabolic traits associated with the 1q25 risk allele in HUVECs, including impairments of the g-glutamyl cycle and methylglyoxal detoxification. Glutamine supplementation abolishes the latter abnormality, suggesting that such treatment may prevent CHD in 1q25 risk allele carriers.

scholarly journals Association of the 1q25 diabetes-specific coronary heart disease locus with alterations of the γ-glutamyl cycle and increased methylglyoxal levels in endothelial cells

2020 ◽  
Author(s):  
Ada Admin ◽  
Caterina Pipino ◽  
Hetal Shah ◽  
Sabrina Prudente ◽  
Natalia Di Pietro ◽  
...  
Keyword(s):  
Coronary Heart Disease ◽  
Endothelial Cells ◽  
Heart Disease ◽  
Glutamic Acid ◽  
Risk Allele ◽  
Umbilical Vein ◽  
Glutamine Supplementation ◽  
Chd Risk ◽  
Umbilical Vein Endothelial Cells

A chromosome 1q25 variant (rs10911021) has been associated with coronary heart disease (CHD) in type 2 diabetes (T2D). In human umbilical vein endothelial cells (HUVECs), the risk allele ‘C’ is associated with lower expression of the adjacent gene <i>GLUL</i> encoding glutamine synthase, converting glutamic acid to glutamine. To further investigate the mechanisms through which this locus affects CHD risk, we measured 35 intracellular metabolites involved in glutamic acid metabolism and g-glutamyl cycle in 62 HUVEC strains carrying different rs10911021 genotypes. Eight metabolites were positively associated with the risk allele (17%-58% increase/allele copy, p=0.046-0.002), including five g-glutamyl amino acids, b-citryl-glutamate, N-acetyl-aspartyl-glutamate, and ophthalmate - a marker of g-glutamyl cycle malfunction. Consistent with these findings, the risk allele was also associated with decreased glutathione/glutamate ratio (-9%, p=0.012), decreased S-lactoylglutathione (-41%, p=0.019), and reduced detoxification of the atherogenic compound methylglyoxal (+54%, p=0.008). <i>GLUL</i> down-regulation by shRNA caused a 40% increase in methylglyoxal level, which was completely prevented by glutamine supplementation. In summary, we have identified intracellular metabolic traits associated with the 1q25 risk allele in HUVECs, including impairments of the g-glutamyl cycle and methylglyoxal detoxification. Glutamine supplementation abolishes the latter abnormality, suggesting that such treatment may prevent CHD in 1q25 risk allele carriers.

scholarly journals Aberrant expression of proatherogenic cytokines and growth factors in human umbilical vein endothelial cells from newborns of type 2 diabetic women

2021 ◽  
Vol 9 ◽  
pp. 205031212110268
Author(s):  
Samar Sultan
Keyword(s):  
Type 2 Diabetes ◽  
Endothelial Cells ◽  
Growth Factors ◽  
Umbilical Vein ◽  
Colony Stimulating Factor ◽  
Human Umbilical Vein ◽  
Normal Glucose ◽  
Umbilical Vein Endothelial Cells ◽  
Stimulating Factor

Objectives: This study reports the levels of cytokines, chemokines, and growth factors previously identified as taking part in the pathology of atherosclerosis in human umbilical vein endothelial cells derived from mothers with type 2 diabetes and compares them with those in human umbilical vein endothelial cells derived from healthy mothers under normal glucose conditions. Methods: Cytokine analysis measures of human umbilical vein endothelial cell lysates were obtained using a multiple analyte profiling (xMAP) assay based on magnetic bead-based technology, using the MAGPIX instrument. The correlation between cytokines, chemokines, and growth factors was examined statistically in human umbilical vein endothelial cells derived from mothers with type 2 diabetes. Results: This study showed that the expression of proinflammatory cytokine interleukin-1 alpha was significantly greater in human umbilical vein endothelial cells derived from mothers with type 2 diabetes than those derived from healthy mothers. The protein level of granulocyte colony-stimulating factor was higher in human umbilical vein endothelial cells derived from mothers with type 2 diabetes than those derived from healthy mothers. A significant positive correlation was demonstrated between the protein expression of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor in human umbilical vein endothelial cells derived from mothers with type 2 diabetes. Conclusion: Diabetes evokes a persistent inflammatory phenotype in human umbilical vein endothelial cells, as indicated by the enhanced production of cytokines and growth factors under normal glucose conditions.

Lipid mediators of autophagy in stress-induced premature senescence of endothelial cells

2008 ◽  
Vol 294 (3) ◽  
pp. H1119-H1129 ◽  
Author(s):  
Susann Patschan ◽  
Jun Chen ◽  
Alla Polotskaia ◽  
Natalja Mendelev ◽  
Jennifer Cheng ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Death ◽  
Umbilical Vein ◽  
Acid Sphingomyelinase ◽  
Premature Senescence ◽  
Human Umbilical Vein ◽  
Glycation End Products ◽  
Umbilical Vein Endothelial Cells ◽  
Stress Induced Premature Senescence

Our group (Patschan S, Chen J, Gealekman O, Krupincza K, Wang M, Shu L, Shayman JA, Goligorsky MS; Am J Physiol Renal Physiol 294: F100–F109, 2008) previously observed an accumulation of gangliosides coincident with development of cell senescence and demonstrated lysosomal permeabilization in human umbilical vein endothelial cells exposed to glycated collagen I (GC). Therefore, we investigated whether the lysosome-dependent, caspase-independent or type 2-programmed cell death (autophagy) is involved in development of premature senescence of endothelial cells. The cleaved microtubule-associated protein 1 light-chain 3 (LC3), a marker of autophagosome formation, was overexpressed within 24 h of GC treatment; however, by 4–5 days, it was nearly undetectable. Early induction of autophagosomes was associated with their fusion with lysosomes, a phenomenon that later became subverted. Autophagic cell death can be triggered by the products of damaged plasma membrane, sphingolipids, and ceramide. We observed a clustering of membrane rafts shortly after exposure to GC; later, after 24 h, we observed an internalization, accompanied by an increased acid sphingomyelinase activity and accumulation of ceramide. Pharmacological inhibition of autophagy prevented development of premature senescence but did lead to the enhanced rate of apoptosis in human umbilical vein endothelial cells exposed to GC. Pharmacological induction of autophagy resulted in reciprocal changes. These observations appear to represent a mechanistic molecular cascade whereby advanced glycation end products like GC induce sphingomyelinase activity, accumulation of ceramide, clustering, and later internalization of lipid rafts.

scholarly journals Association Between a Genetic Variant Related to Glutamic Acid Metabolism and Coronary Heart Disease in Individuals With Type 2 Diabetes

JAMA ◽  
2013 ◽  
Vol 310 (8) ◽  
pp. 821 ◽  
Author(s):  
Lu Qi ◽  
Qibin Qi ◽  
Sabrina Prudente ◽  
Christine Mendonca ◽  
Francesco Andreozzi ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Coronary Heart Disease ◽  
Heart Disease ◽  
Glutamic Acid ◽  
Genetic Variant ◽  
Acid Metabolism

scholarly journals Gender Differences in Risks of Coronary Heart Disease and Stroke in Patients with Type 2 Diabetes Mellitus and Their Association with Metabolic Syndrome in China

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Mei-Fang Yao ◽  
Jie He ◽  
Xue Sun ◽  
Xiao-Li Ji ◽  
Yue Ding ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Metabolic Syndrome ◽  
Coronary Heart Disease ◽  
Type 2 Diabetes Mellitus ◽  
Heart Disease ◽  
Stroke Risk ◽  
Chinese Women ◽  
Chd Risk

Coronary heart disease (CHD) and stroke are common complications of type 2 diabetes mellitus (T2DM). We aimed to explore the differences in the risks of CHD and stroke between Chinese women and men with T2DM and their association with metabolic syndrome (MS). This study included 1514 patients with T2DM. The Asian Guidelines of ATPIII (2005) were used for MS diagnosis, and the UKPDS risk engine was used to evaluate the 10-year CHD and stroke risks. Women had lower CHD risk (15.3% versus 26.3%), fatal CHD risk (11.8% versus 19.0%), stroke risk (8.4% versus 10.3%), and fatal stroke risk (1.4% versus 1.6%) compared with men with T2DM (p<0.05–0.001). The CHD risk (28.4% versus 22.6%, p<0.001) was significantly higher in men with MS than in those without MS. The CHD (16.2% versus 11.0%, p<0.001) and stroke risks (8.9% versus 5.8%, p<0.001) were higher in women with MS than in those without MS. In conclusion, our findings indicated that Chinese women with T2DM are less susceptible to CHD and stroke than men. Further, MS increases the risk of both these events, highlighting the need for comprehensive metabolic control in T2DM.

scholarly journals Prevalence and Risk Factors of Coronary Heart Disease in Chinese Patients with type 2 Diabetes Mellitus, 2013-2018

2020 ◽  
Author(s):  
Chenchen Wang ◽  
Zuoling Xie ◽  
Xi Huang ◽  
Zheng Wang ◽  
Haiyan Shangguan ◽  
...  
Keyword(s):  
Risk Factors ◽  
Type 2 Diabetes ◽  
Coronary Heart Disease ◽  
Regression Analysis ◽  
Heart Disease ◽  
Diabetic Patients ◽  
Population Census ◽  
Chd Risk ◽  
Chd Risk Factors

Abstract Background: Coronary heart disease (CHD) is the most common cause of death in patients with type 2 diabetes (T2DM). We aim to estimate the prevalence of CHD and cardiovascular risk factors in Chinese diabetic inpatients.Methods: A total of 66536 diabetic inpatients from 2013 to 2018 were investigated, demographic and clinical data were gathered from 30693 patients with T2DM. The age-standardized prevalence of CHD was calculated on the basis of data from Chinese population census in 2010. Multiple imputation was used to impute missing values and logistic regression analysis was used to analyze the risk factors.Results: The crude prevalence of CHD was estimated to be 23.5% and a standardized prevalence was 13.9% (16.0% in men and 11.9% in women). More than half of diabetic patients with CHD have 4 or above of the 5 traditional risk factors, which is much higher than 38.96% of diabetic patients (p<0.01). Multivariate regression analysis showed that diabetes duration, hypertension, smoking, underweight, overweight, obesity, hypoglycemia were significantly associated with a higher risk of CHD (all p<0.05). The odds ratio of CHD in patients having 3, 4, or 5 CHD risk factors were 2.35 (95%CI 1.81- 3.04), 2.96 (95%CI 2.28- 3.85), and 5.29 (95%CI 4.04- 6.93), compared with diabetes patients without any other risk factors.Conclusions: The prevalence of CHD was rather high in Chinese T2DM inpatients, aggregation of CHD risk factors was more seriously, hierarchical CHD prevention strategies based on risk factors are needed for them.

scholarly journals Sex Differences in the Risk of Coronary Heart Disease Associated With Type 2 Diabetes: A Mendelian Randomization Analysis

2020 ◽  
Author(s):  
Tricia M. Peters ◽  
Michael V. Holmes ◽  
J. Brent Richards ◽  
Tom Palmer ◽  
Vincenzo Forgetta ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Coronary Heart Disease ◽  
Heart Disease ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Sensitivity Analyses ◽  
Chd Risk ◽  
Unit Increase

<b>Objective</b>: Observational studies have demonstrated that type 2 diabetes is a stronger risk factor for coronary heart disease (CHD) in women compared with men. However, it is not clear whether this reflects a sex differential in the causal effect of diabetes on CHD risk or results from sex-specific residual confounding. <p><b>Methods</b>: Using 270 single nucleotide polymorphisms (SNPs) for type 2 diabetes identified in a type 2 diabetes genome-wide association study, we performed a sex-stratified Mendelian randomization (MR) study of type 2 diabetes and CHD using individual participant data in UK Biobank (N=251,420 women and 212,049 men). Weighted-median, MR Egger, MR-PRESSO and radial MR from summary-level analyses were used for pleiotropy assessment. </p> <p><b>Results</b>: MR analyses showed that genetic risk of type 2 diabetes increased the odds of CHD for women (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.08-1.18 per 1-log unit increase in odds of type 2 diabetes) and men (OR 1.21, 95% CI 1.17-1.26 per 1-log unit increase in odds of type 2 diabetes). Sensitivity analyses showed some evidence of directional pleiotropy, however, results were similar after correction for outlier SNPs.</p> <p><b>Conclusions</b>: This MR analysis supports a causal effect of genetic liability to type 2 diabetes on risk of CHD that is not stronger for women than men. Assuming a lack of bias, these findings suggest that the prevention and management of type 2 diabetes for CHD risk reduction is of equal priority in both sexes.</p>

scholarly journals MicroRNA-451b participates in coronary heart disease by targeting VEGFA

Open Medicine ◽  
2019 ◽  
Vol 15 (1) ◽  
pp. 1-7 ◽  
Author(s):  
Jie Lin ◽  
Jun Jiang ◽  
Ruifang Zhou ◽  
Xiaojie Li ◽  
Jun Ye
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Umbilical Vein ◽  
Luciferase Reporter ◽  
High Morbidity ◽  
Luciferase Reporter Gene ◽  
Gene Assay ◽  
Direct Target Gene ◽  
Artery Disease ◽  
Umbilical Vein Endothelial Cells

AbstractCoronary artery disease (CAD) is one of the main causes of hospitalization worldwide and has high morbidity. MicroRNAs (miRNAs) play an important role in the pathogenesis of cardiovascular diseases. miR-451 is a special miRNA that is involved in many cancers’ development. At present, there is no research about miR-451 in coronary heart disease. In this study, we aimed to identify the action mechanism of miR-451 in coronary heart disease and human umbilical vein endothelial cells (HUVECs). In this study, we found that miR-451 is up-regulated in the peripheral blood of patients with coronary heart disease. Moreover, TargetScan and dual-luciferase reporter gene assay results showed that VEGFA is a direct target gene of miR-451. C (CCK-8) and flow cytometry assay results showed that miR-451 mimic significantly inhibits cell proliferation and promotes apoptosis in HUVECs. Moreover, we found that the role of miR-451 in HUVECs is associated with the PI3K-Akt-mTOR pathway. Taken together, the data indicates that miR-451 might be a novel bio-marker for coronary heart disease.

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