Effect of Short-term Polyphenol Treatment on Endothelial Dysfunction and Thromboxane A2 Levels in Streptozotocin-Induced Diabetic Mice

AbstractIt is well known that high von Willebrand factor (VWF) and factor VIII (FVIII) levels are associated with an increased risk of cardiovascular disease. It is still debated whether VWF and FVIII are biomarkers of endothelial dysfunction and atherosclerosis or whether they have a direct causative role. Therefore, we aimed to unravel the pathophysiological pathways of increased VWF and FVIII levels associated with cardiovascular risk factors. First, we performed a randomized controlled trial in 34 Göttingen miniswine. Diabetes mellitus (DM) was induced with streptozotocin and hypercholesterolemia (HC) via a high-fat diet in 18 swine (DM + HC), while 16 healthy swine served as controls. After 5 months of follow-up, FVIII activity (FVIII:C) was significantly higher in DM + HC swine (5.85 IU/mL [5.00–6.81]) compared with controls (4.57 [3.76–5.40], p = 0.010), whereas VWF antigen (VWF:Ag) was similar (respectively 0.34 IU/mL [0.28–0.39] vs. 0.34 [0.31–0.38], p = 0.644). DM + HC swine had no endothelial dysfunction or atherosclerosis during this short-term follow-up. Subsequently, we performed a long-term (15 months) longitudinal cohort study in 10 Landrace–Yorkshire swine, in five of which HC and in five combined DM + HC were induced. VWF:Ag was higher at 15 months compared with 9 months in HC (0.37 [0.32–0.42] vs. 0.27 [0.23–0.40], p = 0.042) and DM + HC (0.33 [0.32–0.37] vs. 0.25 [0.24–0.33], p = 0.042). Both long-term groups had endothelial dysfunction compared with controls and atherosclerosis after 15 months. In conclusion, short-term hyperglycemia and dyslipidemia increase FVIII, independent of VWF. Long-term DM and HC increase VWF via endothelial dysfunction and atherosclerosis. Therefore, VWF seems to be a biomarker for advanced cardiovascular disease.

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Short-term rhGH increases PIIINP, a biomarker of endothelial dysfunction

International Journal of Advanced Engineering Research and Science ◽

10.22161/ijaers.4.7.26 ◽

2017 ◽

Vol 4 (7) ◽

pp. 164-173

Author(s):

Graham M. R. ◽

Gu Y. ◽

Evans P. J. ◽

Cooper S. M. ◽

Davies B. ◽

...

Keyword(s):

Endothelial Dysfunction ◽

Short Term

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Abstract 890: Feed-forward Signaling of TNF alpha and NFkappa B Produces Endothelial Dysfunction in Coronary Arterioles In Type Ii Diabetic Mice.

Circulation ◽

10.1161/circ.116.suppl_16.ii_174-a ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Jiyeon Yang ◽

Xiangbin Xu ◽

Glen A Laine ◽

Cuihua Zhang

Keyword(s):

Oxidative Stress ◽

Endothelial Dysfunction ◽

Nuclear Factor Κb ◽

Inhibitory Effect ◽

Type Ii ◽

Diabetic Mice ◽

Necrosis Factor Alpha ◽

Paramagnetic Resonance ◽

Feed Forward ◽

Coronary Arterioles

Nuclear factor-κB (NFκB) signaling reportedly increases tumor necrosis factor-alpha (TNF expression), and the oxidative stress induced by TNF may then lead to further increase NFκB expression, i.e., a feed-forward interaction. Accordingly, we hypothesized that this feed-forward interaction between TNF and NFκB may amplify one another toward the evolution of vascular disease in diabetes. To test this hypothesis, we assessed the role of NFκB in endothelial dysfunction in Lepr db mice by evaluation of endothelial function of isolated coronary resistance vessels of m Lepr db (heterozygote, normal) and Lepr db (homozygote, diabetic) mice. Coronary arterioles (40 –100 μm) were isolated and pressurized (60 cmH2O) without flow. Although dilation of vessels to the endothelium-independent vasodilator, sodium nitroprusside (SNP) was not different between Lepr db and m Lepr db mice (n = 6), dilation to the endothelium-dependent agonist, acetycholine (ACh) was reduced (n = 5, P < 0.05). Electron Paramagnetic Resonance (EPR) results show that superoxide production was reduced by NFκB antagonist (MG-132), or anti-TNF in Lepr db mice suggesting that NFκB and TNF were contributing to elevated oxidative stress. MG-132 (1 μM, n = 4) antagonized the inhibitory effect of Lepr db mice on ACh-induced dilation vs. Lepr db without treatment, but did not affect dilation in m Lepr db mice. To better understand the basis for enhanced contributions of TNF and NFκB in diabetes, we used Western analysis to assess expression of major proteins involved in TNF-mediated signaling. Previous studies have provided compelling evidence that IKK beta plays an essential role in NFκB activation in response to TNF, whereas IKK alpha appears to play a lesser role; therefore, we examined the expression levels of IKK alpha and IKK beta mRNA and protein in Lepr db null for TNF. The protein concentration and mRNA expression level of IKK alpha were increased in Lepr db mice null for TNF (db TNF- /db TNF- ) mice. One intriguing finding of this study is that the roles of IKK alpha and IKK beta appear reversed in the inflammatory response in diabetic Lepr db mice. Furthermore, our results indicate that NFκB and TNF signaling interact to amplify the oxidative stress and induce endothelial dysfunction in type II diabetes.

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Abstract 879: Aldehyde Dehydrogenase Activator 1 (Alda-1) Attenuates Coronary Endothelial Dysfunction-Mediated Cardiac Damage in ALDH2*2 Diabetic Mice

Circulation Research ◽

10.1161/res.125.suppl_1.879 ◽

2019 ◽

Vol 125 (Suppl_1) ◽

Author(s):

Guodong Pan ◽

Haiyan Pang ◽

Mandar Deshpande ◽

Suresh Palaniyandi

Keyword(s):

Endothelial Dysfunction ◽

Aldehyde Dehydrogenase ◽

Diabetic Mice ◽

Cardiac Damage ◽

Coronary Endothelial Dysfunction

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O-GlcNAcase overexpression reverses coronary endothelial cell dysfunction in type 1 diabetic mice

AJP Cell Physiology ◽

10.1152/ajpcell.00069.2015 ◽

2015 ◽

Vol 309 (9) ◽

pp. C593-C599 ◽

Cited By ~ 26

Author(s):

Ayako Makino ◽

Anzhi Dai ◽

Ying Han ◽

Katia D. Youssef ◽

Weihua Wang ◽

...

Keyword(s):

Endothelial Cells ◽

Endothelial Dysfunction ◽

Endothelial Function ◽

Protein Modification ◽

Control Level ◽

Vascular Complications ◽

Capillary Density ◽

Diabetic Mice ◽

Endothelium Dependent Relaxation

Cardiovascular disease is the primary cause of morbidity and mortality in diabetes, and endothelial dysfunction is commonly seen in these patients. Increased O-linked N-acetylglucosamine ( O-GlcNAc) protein modification is one of the central pathogenic features of diabetes. Modification of proteins by O-GlcNAc ( O-GlcNAcylation) is regulated by two key enzymes: β- N-acetylglucosaminidase [ O-GlcNAcase (OGA)], which catalyzes the reduction of protein O-GlcNAcylation, and O-GlcNAc transferase (OGT), which induces O-GlcNAcylation. However, it is not known whether reducing O-GlcNAcylation can improve endothelial dysfunction in diabetes. To examine the effect of endothelium-specific OGA overexpression on protein O-GlcNAcylation and coronary endothelial function in diabetic mice, we generated tetracycline-inducible, endothelium-specific OGA transgenic mice, and induced OGA by doxycycline administration in streptozotocin-induced type 1 diabetic mice. OGA protein expression was significantly decreased in mouse coronary endothelial cells (MCECs) isolated from diabetic mice compared with control MCECs, whereas OGT protein level was markedly increased. The level of protein O-GlcNAcylation was increased in diabetic compared with control mice, and OGA overexpression significantly decreased the level of protein O-GlcNAcylation in MCECs from diabetic mice. Capillary density in the left ventricle and endothelium-dependent relaxation in coronary arteries were significantly decreased in diabetes, while OGA overexpression increased capillary density to the control level and restored endothelium-dependent relaxation without changing endothelium-independent relaxation. We found that connexin 40 could be the potential target of O-GlcNAcylation that regulates the endothelial functions in diabetes. These data suggest that OGA overexpression in endothelial cells improves endothelial function and may have a beneficial effect on coronary vascular complications in diabetes.

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