Endothelial dysfunction in the streptozotocin‐induced diabetic apoE‐deficient mouse

Ding, Hong; Hashem, Michael; Wiehler, William B.; Lau, W.B.; Martín, Jacqueline M.; Reid, Julianne J.; Triggle, Chris R.

doi:10.1038/sj.bjp.0706417

Cited by 92 publications

(85 citation statements)

References 67 publications

(82 reference statements)

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“…This suggests baseline endothelial SK3 levels are not rate limiting for EDHinduced vasodilation in normal physiological conditions but could become so when the EDH pathway needs to be activated, e.g., during early diabetes. SK3 downregulation was previously observed in STZ-induced diabetic ApoE-deficient mice (22) or in the cavernous tissues of diabetic rats (32) but not in C57Bl/6 diabetic mice (27). In line with the latter results, SK3 was not downregulated by diabetes in our study.…”

Section: Lack Of Hyal1 Prevents Endothelial Dysfunctionsupporting

confidence: 81%

“…The mRNA expression level of several components of the EDH pathway (22) in mesenteric arteries was screened using real-time RT-PCR. No difference among experimental groups was detected for connexins 37, 40, 43, and 45; SK channels SK1 and SK2; intermediate conductance potassium channel IK1; transient receptor potential (TRP) channels TRPV4 and TRPC1; and caveolin-1 (data not shown).…”

Section: Exploration Of the Edh Pathway Componentsmentioning

confidence: 99%

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Hyaluronidase 1 Deficiency Preserves Endothelial Function and Glycocalyx Integrity in Early Streptozotocin-Induced Diabetes

et al. 2016

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Hyaluronic acid (HA) is a major component of the glycocalyx involved in the vascular wall and endothelial glomerular permeability barrier. Endocytosed hyaluronidase HYAL1 is known to degrade HA into small fragments in different cell types, including endothelial cells. In diabetes, the size and permeability of the glycocalyx are altered. In addition, patients with type 1 diabetes present increased plasma levels of both HA and HYAL1. To investigate the potential implication of HYAL1 in the development of diabetes-induced endothelium dysfunction, we measured endothelial markers, endothelium-dependent vasodilation, arteriolar glycocalyx size, and glomerular barrier properties in wild-type and HYAL1 knockout (KO) mice with or without streptozotocin (STZ)-induced diabetes. We observed that 4 weeks after STZ injections, the lack of HYAL1 1) prevents diabetes-induced increases in soluble P-selectin concentrations and limits the impact of the disease on endothelium-dependent hyperpolarization (EDH)-mediated vasorelaxation; 2) increases glycocalyx thickness and maintains glycocalyx structure and HA content during diabetes; and 3) prevents diabetes-induced glomerular barrier dysfunction assessed using the urinary albumin-to-creatinine ratio and urinary ratio of 70-to 40-kDa dextran. Our findings suggest that HYAL1 contributes to endothelial and glycocalyx dysfunction induced by diabetes. HYAL1 inhibitors could be explored as a new therapeutic approach to prevent vascular complications in diabetes.

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Section: Lack Of Hyal1 Prevents Endothelial Dysfunctionsupporting

confidence: 81%

Section: Exploration Of the Edh Pathway Componentsmentioning

confidence: 99%

Hyaluronidase 1 Deficiency Preserves Endothelial Function and Glycocalyx Integrity in Early Streptozotocin-Induced Diabetes

et al. 2016

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“…Gap junction pathways in retinal arteries [45] and gap junction activity in mesenteric arteries [24] from STZ-induced diabetic rats have been shown to be reduced, and Ding et al [46] demonstrated that Cx37 mRNA expression was reduced in small mesenteric arteries from STZ-induced diabetic apoEdeficient mice compared with nondiabetic apoE-deficient control mice. Furthermore, we have shown a decrease in gap junction activity in isolated renal arteries from the female 25-week-old OZRs, associated with decreases in connexin 40 protein levels and Cx40 mRNA expression (E. J Young and J. J Reid, unpublished data).…”

Section: Discussionmentioning

confidence: 99%

Reduced EDHF responses and connexin activity in mesenteric arteries from the insulin-resistant obese Zucker rat

et al. 2008

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Aims/hypothesis The objective of this study was to examine the effect of insulin resistance on endothelium-derived hyperpolarising factor (EDHF) and small mesenteric artery endothelial function using 25-week-old insulin-resistant obese Zucker rats (OZRs) and lean littermate control rats (LZRs). The involvement of gap junctions and their connexin subunits in the EDHF relaxation response was also assessed. Methods Mesenteric arteries were evaluated using the following assays: (1) endothelial function by pressure myography, with internal diameter recorded using video microscopy; (2) connexin protein levels by western blotting; and (3) Cx mRNA expression by real-time PCR. Results Relaxations in response to acetylcholine were significantly smaller in mesenteric arteries from the OZRs than the LZRs, whereas there was no difference in relaxations in response to levcromakalim. Responses to acetylcholine were not altered by nitric oxide inhibitors, but were abolished by charybdotoxin in combination with apamin, which blocked the EDHF component of the response. 40 Gap27 significantly attenuated the response to acetylcholine in the LZRs, but had no effect in the OZRs. Connexin 40 protein and Cx40 mRNA levels in mesenteric vascular homogenates were significantly smaller in the OZRs than in the LZRs, with no difference in connexin 43 or Cx43 mRNA levels. Conclusions/interpretation These findings demonstrate that endothelial dysfunction in mesenteric arteries from the insulin-resistant OZRs can be attributed to a defect in EDHF. The results also suggest that the defective EDHF is at least partly related to an impairment of connexin 40-associated gap junctions, through a decrease in connexin 40 protein and Cx40 mRNA expression in the OZRs.

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“…Furthermore, it has to be emphasized that changes in Cx expression and function may not be the sole contributors to endothelial dysfunction, and multiple mechanisms contribute to the inhibited coronary vasodilatation in diabetic mice. In addition to the impaired GJIC by decreased Cx40 expression, we believe that the inhibited endothelium-dependent hyperpolarization in diabetic CA may also involve other mechanisms: for example, 1) dysfunctional coupling of Cx peptides and their spatial co-association with K ϩ channels (12,42), and 2) changes in expression and activity K ϩ channels in the vascular smooth muscle cells (13,26).…”

Section: Discussionmentioning

confidence: 99%

Downregulation of connexin40 is associated with coronary endothelial cell dysfunction in streptozotocin-induced diabetic mice

Platoshyn

Suárez

Yuan

et al. 2008

American Journal of Physiology-Cell Physiology

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Dillmann WH. Downregulation of connexin40 is associated with coronary endothelial cell dysfunction in streptozotocin-induced diabetic mice. Am J Physiol Cell Physiol 295: C221-C230, 2008. First published May 7, 2008 doi:10.1152/ajpcell.00433.2007.-Vascular endothelial cells (ECs) play a major role in regulating vascular tone and in revascularization. There is increasing evidence showing endothelial dysfunction in diabetes, although little is known about the contribution of connexins (Cxs) to vascular complications in the diabetic heart. This study was designed to investigate the role of Cxs in coronary endothelial dysfunction in diabetic mice. Coronary ECs isolated from diabetic mice exhibit lowered protein levels of Cx37 and Cx40 (but not Cx43) and a loss of gap junction intercellular communication (GJIC). Vasodilatation induced by the assumed contribution of ECdependent hyperpolarization was significantly reduced in the diabetic coronary artery (CA). Cx40-specific inhibitory peptide 40 GAP27 strongly attenuated endothelium-dependent relaxation in diabetic CA at the concentration that does not affect the relaxation in control CA, suggesting that the total amount of Cx40 is lower in diabetic CA than in control CA. In diabetic mice, coronary capillary density was significantly decreased in vivo. In vitro, GJIC inhibitor attenuated the ability of EC capillary network formation. High-glucose treatment caused a decrease in Cx40 protein expression in ECs and impaired endothelial capillary network formation, which was restored by Cx40 overexpression. Furthermore, we found that the hyperglycemia-induced decrease in Cx40 was associated with inhibited protein expression of Sp1, a transcriptional factor that regulates Cx40 expression. These data suggest that downregulation of Cx40 protein expression and resultant inhibition of GJIC contribute to coronary vascular dysfunction in diabetes.

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Endothelial dysfunction in the streptozotocin‐induced diabetic apoE‐deficient mouse

Cited by 92 publications

References 67 publications

Hyaluronidase 1 Deficiency Preserves Endothelial Function and Glycocalyx Integrity in Early Streptozotocin-Induced Diabetes

Hyaluronidase 1 Deficiency Preserves Endothelial Function and Glycocalyx Integrity in Early Streptozotocin-Induced Diabetes

Reduced EDHF responses and connexin activity in mesenteric arteries from the insulin-resistant obese Zucker rat

Downregulation of connexin40 is associated with coronary endothelial cell dysfunction in streptozotocin-induced diabetic mice

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