Abstract P127: Adverse Endothelial Cell Protein Expression is Associated With Type 1 Diabetes

Circulation ◽  
2020 ◽  
Vol 141 (Suppl_1) ◽  
Author(s):  
Amena Keshawarz ◽  
Martin Cech ◽  
Teresa Witten ◽  
Young-Min Park ◽  
Jason Richards ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Endothelial Cell ◽  
Linear Regression ◽  
Protein Expression ◽  
Umbilical Vein ◽  
Cell Protein ◽  
Enos Expression ◽  
Quantitative Immunofluorescence ◽  
Age And Sex

Cardiovascular risk is increased in adults with type 1 diabetes (T1D), although the mechanism is poorly understood. Endothelial dysfunction may contribute to increased coronary artery calcium (CAC) in T1D, and CAC severity may be associated with reduced nitric oxide (NO) synthesis and/or increased inflammation. We tested the hypotheses that high CAC and T1D are associated with expression of endothelial NO synthase (eNOS, enzyme that produces NO), phosphorylated eNOS (p-eNOS), and NFκB (pro-inflammatory transcription factor). Participants were categorized as having high (>80 Agatston units [AU]) or low CAC (<15 AU), measured by CT scan. Protein expression was measured using quantitative immunofluorescence in endothelial cells harvested from 14 women with T1D (mean age 52±8 years; 7 high CAC); 13 men with T1D (mean age 58±7 years; 5 high CAC); 10 women without diabetes (mean age 61±4 years; 3 high CAC); and 10 men without diabetes (mean age 59±6 years; 4 high CAC). All analyses used ratios of endothelial cell protein expression to control human umbilical vein endothelial cell protein expression. Independent t-tests compared protein expression by sex and T1D. Linear regression tested the associations of high vs. low CAC and T1D with the 3 proteins of interest after adjustment for age and sex. In men, eNOS expression differed by T1D: men with T1D had reduced cytoplasmic (0.34 vs.0.52, p=0.03) and nuclear (0.44 vs. 0.60, p=0.02) eNOS expression compared with men without T1D, suggesting reduced NO synthesis. There were no differences in p-eNOS expression, indicating that eNOS levels were likely not due to differential activation. In women, NFκB expression similarly differed by T1D: women with T1D had higher cytoplasmic (0.81 vs. 0.63, p=0.01) and nuclear (0.99 vs. 0.75, p=0.01) NFκB expression compared with women without T1D, suggesting greater inflammation. After adjustment for age and sex, there was no significant association between high vs. low CAC in endothelial expression of any proteins. The data trend suggested that high vs. low CAC is associated with reduced cytoplasmic (0.36 vs. 0.47, p=0.06) and nuclear (0.48 vs. 0.55, p=0.12) eNOS expression. T1D trended in the same direction for both cytoplasmic (0.36 vs. 0.47, p=0.06) and nuclear (0.47 vs. 0.55, p=0.13) eNOS expression. High vs. low CAC also trended towards an association with greater cytoplasmic (0.72 vs. 0.66, p=0.21) and nuclear (0.85 vs. 0.80, p=0.40) NFκB expression, while T1D was significantly associated with greater cytoplasmic (0.76 vs. 0.63, p=0.006) and nuclear (0.92 vs. 0.73, p=0.003) NFκB expression. Neither CAC nor T1D was associated with p-eNOS expression in linear regression. In conclusion, eNOS and NFκB expression are potential mechanisms for increased CAC given their roles in reduced NO synthesis and increased inflammation, and may differ by sex in people with T1D. Regardless of high CAC, inflammation in T1D is increased.

Inhibition of adenosine kinase induces expression of VEGF mRNA and protein in myocardial myoblasts

2000 ◽  
Vol 279 (5) ◽  
pp. H2116-H2123 ◽  
Author(s):  
Jian-Wei Gu ◽  
Bruce R. Ito ◽  
Amanda Sartin ◽  
Nan Frascogna ◽  
Michael Moore ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cell ◽  
Protein Expression ◽  
Kinase Inhibitor ◽  
Umbilical Vein ◽  
Adenosine Kinase ◽  
Endothelial Cell Proliferation ◽  
Cell Protein ◽  
Vegf Mrna ◽  
Vegf Protein

We tested whether increased endogenous adenosine produced by the adenosine kinase inhibitor GP-515 (Metabasis Therapeutics) can induce vascular endothelial growth factor (VEGF) expression in cultured rat myocardial myoblasts (RMMs). RMMs were cultured for 18 h in the absence (control) and presence of GP-515, adenosine (Ado), adenosine deaminase (ADA), or GP-515 + ADA. GP-515 (0.2–200 μM) caused a dose-related increase in VEGF protein expression (1.99–2.84 ng/mg total cell protein); control VEGF was 1.84 ± 0.05 ng/mg. GP-515 at 2 and 20 μM also increased VEGF mRNA by 1.67- and 1.82-fold, respectively. ADA (10 U/ml) decreased baseline VEGF protein levels by 60% and completely blocked GP-515 induction of VEGF. Ado (20 μM) and GP-515 (20 μM) caused a 59 and 39% increase in VEGF protein expression and a 98 and 33% increase in human umbilical vein endothelial cell proliferation, respectively, after 24 h of exposure. GP-515 (20 μM) had no effect on VEGF protein expression during severe hypoxia (1% O2) but increased VEGF by an additional 27% during mild hypoxia (10% O2). These results indicate that raising endogenous levels of Ado through inhibition of adenosine kinase can increase the expression of VEGF and stimulate endothelial cell proliferation during normoxic and hypoxic conditions.

Abstract 352: Myocardial Neuregulin-1/ErbB Signaling Is Impaired in the Setting of Post--Myocardial Infarction Heart Failure Complicated by Type 1 Diabetes Mellitus

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Oghenerukevwe Odiete ◽  
Kathleen E Dennis ◽  
Douglas B Sawyer ◽  
Michael F Hill
Keyword(s):  
Diabetes Mellitus ◽  
Myocardial Infarction ◽  
Heart Failure ◽  
Type 1 Diabetes ◽  
Protein Expression ◽  
Type 1 Diabetes Mellitus ◽  
Neuregulin 1 ◽  
Erbb Signaling ◽  
Type 1 Dm

Background: Type 1 diabetes mellitus (DM) patients surviving myocardial infarction (MI) are at heightened risk for the subsequent development of heart failure (HF). Despite the worse outcomes, investigations into the pathophysiological mechanisms that contribute to the increased frequency of HF after MI in the type 1 DM heart remain scarce. Neuregulin-1 (NRG-1), along with the ErbB family of receptor tyrosine kinases through which NRG-1 ligands signal, have been shown to be intimately involved in mediating cardiac recovery after MI. However, the impact of type 1 DM on this signaling system post-MI remains to be elucidated. Therefore, in the present study, we examined myocardial NRG-1/ErbB signaling during post-MI HF in the presence of type 1 DM. Methods: Type 1 DM was induced in male Sprague-Dawley rats via a single intraperitoneal injection of streptozotocin (STZ) (65 mg/kg). Two weeks after induction of type 1 DM, MI was produced in DM and non-DM rats by ligation of the left anterior descending (LAD) coronary artery. Residual left ventricular (LV) function was assessed by echocardiography at 4 weeks post-MI. Following echocardiographic assessment, NRG-1, ErbB2, and ErbB4 protein expression was assessed in the remote, surviving LV myocardium of DM and non-DM rats using Western blot techniques. Results: LV Fractional Shortening (FS) and LV Ejection Fraction (EF) were significantly lower in the DM + MI group compared to the MI group ([LVFS: DM + MI, 17.9 ± 0.7 (n=6) vs. MI, 25.2 ± 2.2 (n=6), p <0.05; LVEF: DM + MI, 35.5 ± 1.4 (n=6) vs. MI, 47.5 ± 3.5 (n=6), p <0.05]), indicating an increased functional severity of HF in the diabetic post-MI group. The weight of myocardial scar caused by the infarction was not significantly different between the MI groups ([DM + MI, 0.19 ± 0.02 g (n=4) vs. MI, 0.20 ± 0.03 g (n=4), p =0.70]). ErbB2, ErbB4, and NRG-1 protein expression levels were all significantly lower in the DM + MI group compared to the MI group. Conclusions: These findings demonstrate that type 1 DM impairs myocardial NRG-1/ErbB signaling in response to MI, which may contribute to the accelerated progression of subsequent HF. Augmentation of NRG-1 or its downstream signaling pathways may represent a novel therapeutic strategy for ameliorating post-MI HF in the setting of type 1 DM.

68-OR: Artificial Intelligence and Disparities in Pediatric Type 1 Diabetes Care: Predictive Model Performance Varies by Age and Sex

Diabetes ◽  
2021 ◽  
Vol 70 (Supplement 1) ◽  
pp. 68-OR
Author(s):  
DIANA FERRO ◽  
DAVID D. WILLIAMS ◽  
SUSANA R. PATTON ◽  
RYAN MCDONOUGH ◽  
MARK A. CLEMENTS
Keyword(s):  
Artificial Intelligence ◽  
Type 1 Diabetes ◽  
Predictive Model ◽  
Diabetes Care ◽  
Model Performance ◽  
Pediatric Type 1 Diabetes ◽  
Age And Sex

Hypoxia-induced expression of complement receptor type 1 (CR1, CD35) in human vascular endothelial cells

1999 ◽  
Vol 276 (2) ◽  
pp. C450-C458 ◽  
Author(s):  
Charles D. Collard ◽  
Cuneyt Bukusoglu ◽  
Azin Agah ◽  
Sean P. Colgan ◽  
Wende R. Reenstra ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Protein Expression ◽  
Vascular Endothelial Cells ◽  
Umbilical Vein ◽  
Receptor Type ◽  
Complement Receptor ◽  
Complement Receptor Type ◽  
Umbilical Vein Endothelial Cells ◽  
Complement Receptor Type 1

Reoxygenation of hypoxic human umbilical vein endothelial cells (HUVECs) increases protein expression of the complement regulators CD46 and CD55. As the receptor for C3b is known to be present on injured bovine endothelial cells, we investigated whether hypoxia or inflammatory mediators induce complement receptor type 1 (CR1; CD35) expression on HUVECs. CR1 protein expression increased 3.7 ± 0.6-fold as measured by ELISA on HUVECs following hypoxia (48 h, 1% O2). Colocalization of CD35 and von Willebrand factor by confocal microscopy confirmed that CD35 was predominantly intracellular. Lipopolysaccharide or tumor necrosis factor-α also significantly increased HUVEC CR1 protein expression. Western blot analysis of neutrophil or hypoxic HUVEC lysates revealed a 221-kDa CR1 band under nonreducing conditions. RT-PCR of hypoxic HUVEC mRNA revealed a single band that, after sequencing, was identified as CD35. In situ hybridization of hypoxic HUVECs, but not normoxic HUVECs or fibroblasts, demonstrated increased CD35 mRNA. Hypoxic HUVECs bound immune complexes and acted as a cofactor for factor I-mediated cleavage of C3b. Thus hypoxia induces functional HUVEC CR1 expression.

scholarly journals Bone Mineral Density across the Lifespan in Patients with Type 1 Diabetes

2019 ◽  
Vol 105 (3) ◽  
pp. 746-753 ◽  
Author(s):  
Eitan Halper-Stromberg ◽  
Tyler Gallo ◽  
Anagha Champakanath ◽  
Iman Taki ◽  
Marian Rewers ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Body Mass Index ◽  
Type 1 Diabetes ◽  
Lumbar Spine ◽  
Femoral Neck ◽  
Postmenopausal Women ◽  
Age Groups ◽  
Mineral Density ◽  
Age And Sex

Abstract Context Fracture risk in people with type 1 diabetes (T1D) is higher than their peers without diabetes. Objective To compare bone mineral density (BMD) across the lifespan in individuals with T1D and age- and sex-matched healthy controls. Design Cross-sectional. Setting Subjects (5–71 years) with T1D and matched controls from ongoing research studies at Barbara Davis Center for Diabetes. Patients or other participants Participants with lumbar spine BMD by dual X-ray absorptiometry (DXA) were divided into 2 groups: children ≤20 years and adults &gt;20 years. Intervention None. Main outcome measures Comparison of BMD by diabetes status across age groups and sex using a linear least squares model adjusted for age and body mass index (body mass index (BMI) for adults; and BMI z-score in children). Results Lumbar spine BMD from 194 patients with T1D and 156 controls were analyzed. There was no difference in age- and BMI-adjusted lumbar spine BMD between patients with T1D and controls: among male children (least squares mean ± standard error of the mean [LSM ± SEM]; 0.80 ± 0.01 vs 0.80 ± 0.02 g/cm2, P = .98) or adults (1.01 ± 0.03 vs 1.01 ± 0.03 g/cm2, P = .95), and female children (0.78 ± 0.02 vs 0.81 ± 0.02 g/cm2, P = .23) or adults (0.98 ± 0.02 vs 1.01 ± 0.02 g/cm2, P = .19). Lumbar spine (0.98 ± 0.02 vs 1.04 ± 0.02 g/cm2, P = .05), femoral neck (0.71 ± 0.02 vs 0.79 ± 0.02 g/cm2, P = .003), and total hip (0.84 ± 0.02 vs 0.91 ± 0.02, P = .005) BMD was lower among postmenopausal women with T1D than postmenopausal women without diabetes. Conclusion Across age groups, lumbar spine BMD was similar in patients with T1D compared with age- and sex-matched participants without diabetes, except postmenopausal females with T1D had lower lumbar spine, femoral neck, and total hip BMD.

scholarly journals Proteomic changes associated with diabetes in the BB-DP rat

2009 ◽  
Vol 296 (3) ◽  
pp. E422-E432 ◽  
Author(s):  
D. Thor Johnson ◽  
Robert A. Harris ◽  
Stephanie French ◽  
Angel Aponte ◽  
Robert S. Balaban
Keyword(s):  
Mass Spectrometry ◽  
Skeletal Muscle ◽  
Type 1 Diabetes ◽  
Protein Expression ◽  
Gel Electrophoresis ◽  
Citrate Synthase ◽  
Carbon Substrate ◽  
2D Gel Electrophoresis ◽  
2D Gel

These studies were structured with the aim of utilizing emerging technologies in two-dimensional (2D) gel electrophoresis and mass spectrometry to evaluate protein expression changes associated with type 1 diabetes. We reasoned that a broad examination of diabetic tissues at the protein level might open up novel avenues of investigation of the metabolic and signaling pathways that are adversely affected in type 1 diabetes. This study compared the protein expression of the liver, heart, and skeletal muscle of diabetes-prone rats and matched control rats by semiquantitative liquid chromatography-mass spectrometry and differential in-gel 2D gel electrophoresis. Differential expression of 341 proteins in liver, 43 in heart, and 9 (2D gel only) in skeletal muscle was detected. These data were assembled into the relevant metabolic pathways affected primarily in liver. Multiple covalent modifications were also apparent in 2D gel analysis. Several new hypotheses were generated by these data, including mechanisms of net cytosolic protein oxidation, formaldehyde generation by the methionine cycle, and inhibition of carbon substrate oxidation via reduction in citrate synthase and short-chain acyl-CoA dehydrogenase.

Persistence of Serum Antibodies to 64,000-Mr Islet Cell Protein After Onset of Type 1 Diabetes

Diabetes ◽  
1990 ◽  
Vol 39 (6) ◽  
pp. 653-656 ◽  
Author(s):  
M. R. Christie ◽  
D. Daneman ◽  
P. Champagne ◽  
T. L. Delovitch
Keyword(s):  
Type 1 Diabetes ◽  
Islet Cell ◽  
Cell Protein ◽  
Serum Antibodies
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