GLP-1 Inhibits High-Glucose-Induced Oxidative Injury of Vascular Endothelial Cells

Quan, Li; Lin, Yajun; Wang, Shu; Zhang, Lina; Guo, Lixin

doi:10.1038/s41598-017-06712-z

Cited by 53 publications

(40 citation statements)

References 23 publications

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“…Although it is well known that HG plays a key role in diabetic endothelial dysfunction and atherosclerosis, the mechanisms responsible for HG-induced endothelial damage remain to be elucidated. The HG (33 mM)-induced HUVECs injury model was employed to investigate the underlying mechanisms of endothelial injury, and further investigated cytoprotection of H 2 S. In the present study, HG treatment for 24 hrs caused a significant reduction in the cell viability of HUVECs, which was consistent with the results from Han et al, 34 However, several studies demonstrated that the inhibitory effects of HG on HUVEC viability were observed after 48-hr 35 and 72-hr treatment. [36][37][38][39] The inconsistency regarding the HG treatment duration across different studies may be due to the different culture conditions, different sources for obtaining HUVECs, or different experimental protocols, which may require further examination.…”

Section: Discussionsupporting

confidence: 91%

<p>Hydrogen Sulfide Protects Against High Glucose-Induced Human Umbilical Vein Endothelial Cell Injury Through Activating PI3K/Akt/eNOS Pathway</p>

Lin

Yang

Wei

et al. 2020

DDDT

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Dysfunction of endothelial cells plays a key role in the pathogenesis of diabetic atherosclerosis. High glucose (HG) has been found as a key factor in the progression of diabetic complications, including atherosclerosis. PI3K/Akt/eNOS signaling pathway has been shown to involve in HG-induced vascular injuries. Hydrogen sulfide (H 2 S) has been found to exhibit protective effects on HG-induced vascular injuries. Moreover, H 2 S activates PI3K/Akt/eNOS pathway in endothelial cells. Thus, the present study aimed to determine if H 2 S exerts protective effects against HG-induced injuries of human umbilical vein endothelial cells (HUVECs) via activating PI3K/Akt/eNOS signaling. Materials and Methods: The endothelial protective effects of H 2 S were evaluated and compared to the controlled groups. Cell viability, cell migration and tube formation were determined by in vitro functional assays; protein levels were evaluated by Western blot assay and ELISA; cell apoptosis was determined by Hoechst 33258 nuclear staining; Reactive oxygen species (ROS) production was evaluated by the ROS detection kit. Results: HG treatment significantly inhibited PI3K/Akt/eNOS signaling in HUVECs, which was partially reversed by the H2S treatment. HG treatment inhibited cell viability of HUVECs, which were markedly prevented by H 2 S or PI3K agonist Y-P 740. HG treatment also induced HUVEC cell apoptosis by increasing the protein levels of cleaved caspase 3, Bax and Bcl-2, which were significantly attenuated by H 2 S or 740 Y-P. ROS production and gp91 phox protein level were increased by HG treatment in HUVECs and this effect can be blocked by the treatment with H 2 S or Y-P 740. Moreover, HG treatment increased the protein levels of pro-inflammatory cytokines, caspase-1 and phosphorylated JNK, which was significantly attenuated by H 2 S or Y-P 740. Importantly, the cytoprotective effect of H 2 S against HG-induced injury was inhibited by LY294002 (an inhibitor of PI3K/Akt/eNOS signaling pathway). Conclusion: The present study demonstrated that exogenous H 2 S protects endothelial cells against HG-induced injuries by activating PI3K/Akt/eNOS pathway. Based on the above findings, we proposed that reduced endogenous H 2 S levels and the subsequent PI3K/Akt/ eNOS signaling impairment may be the important pathophysiological mechanism underlying hyperglycemia-induced vascular injuries.

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Section: Discussionsupporting

confidence: 91%

<p>Hydrogen Sulfide Protects Against High Glucose-Induced Human Umbilical Vein Endothelial Cell Injury Through Activating PI3K/Akt/eNOS Pathway</p>

Lin

Yang

Wei

et al. 2020

DDDT

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“…Such positive correlations were absent in Panx1-400A non-obese individuals. Elevated triglyceride levels as well as increased glucose and insulin concentrations are known to induce endothelial dysfunction by increasing inflammation, apoptosis, and mainly by increasing reactive oxygen species production [32][33][34]. The latter processes have all three been shown to be affected by Panx1 expression or Panx1 channel functionality.…”

Section: Discussionmentioning

confidence: 99%

A Genetic Polymorphism in the Pannexin1 Gene Predisposes for The Development of Endothelial Dysfunction with Increasing BMI

et al. 2020

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Endothelial dysfunction worsens when body mass index (BMI) increases. Pannexin1 (Panx1) ATP release channels regulate endothelial function and lipid homeostasis in mice. We investigated whether the Panx1-400A>C single nucleotide polymorphism (SNP), encoding for a gain-of-function channel, associates with endothelial dysfunction in non-obese and obese individuals. Myocardial blood flow (MBF) was measured by 13N-ammonia positron emission/computed tomography at rest, during cold pressor test (CPT) or dipyridamole-induced hyperemia. Myocardial flow reserve (MFR) and endothelial function were compared in 43 non-obese (BMI < 30 kg/m2) vs. 29 obese (BMI ≥ 30 kg/m2) participants and genotyping for the Panx1-400A>C SNP was performed. Groups comprised subjects homozygous for the C allele (n = 40) vs. subjects with at least one A allele (n = 32). MBF (during CPT or hyperemia), MFR and endothelial function correlated negatively with BMI in the full cohort. BMI correlated negatively with MFR and endothelial function in non-obese Panx1-400C subjects, but not in Panx1-400A individuals nor in obese groups. BMI correlated positively with serum triglycerides, insulin or HOMA. MFR correlated negatively with these factors in non-obese Panx1-400C but not in Panx1-400A individuals. Here, we demonstrated that Panx1-400C SNP predisposes to BMI-dependent endothelial dysfunction in non-obese subjects. This effect may be masked by excessive dysregulation of metabolic factors in obese individuals.

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“…Antihyperglycemic medications are commonly used to normalize glucose levels and include biguanides (metformin), glitazones, dipeptidyl peptidase-4 (DDP-4) inhibitors, and glucagonlike peptide-1 (GLP-1) agonists. With respect to ROS, NOX inhibition, NOS recoupling, and activation of endogenous antioxidant enzymes are all suggested mechanisms of action of these drugs [78][79][80][81]. Metformin is the first-line therapy for T2DM patients and is being tested in several clinical trials (more than 2000 on https://www.clinicaltrials.org) in diabetic and nondiabetic conditions, including cancer.…”

Section: Glucose-lowering Drugsmentioning

confidence: 99%

Reactive Oxygen Comes of Age: Mechanism-Based Therapy of Diabetic End-Organ Damage

Elbatreek

Pachado

Cuadrado

et al. 2019

Trends in Endocrinology & Metabolism

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Reactive oxygen species (ROS) have been mainly viewed as unwanted byproducts of cellular metabolism, oxidative stress, a sign of a cellular redox imbalance, and potential disease mechanisms, such as in diabetes mellitus (DM). Antioxidant therapies, however, have failed to provide clinical benefit. This paradox can be explained by recent discoveries that ROS have mainly essential signaling and metabolic functions and evolutionally conserved physiological enzymatic sources. Disease can occur when ROS accumulate in nonphysiological concentrations, locations, or forms. By focusing on disease-relevant sources and targets of ROS, and leaving ROS physiology intact, precise therapeutic interventions are now possible and are entering clinical trials. Their outcomes are likely to profoundly change our concepts of ROS in DM and in medicine in general. A New Approach to Diabetes Mellitus and Reactive Oxygen Species Diabetes mellitus (DM) and its related end-organ damage, such as diabetic nephropathy, neuropathy, retinopathy, and cardiomyopathy, are major causes of death and long-term disability. Their underlying mechanisms are incompletely understood, which is why none of the current antidiabetic therapies target the underlying causes or are curative, but focus instead on normalizing surrogate parameters or risk factors such as blood glucose or hypertension [1]. Hence, our lack of mechanistic understanding of lifestyle change-resistant diabetic end-organ damage, together with the increasing prevalence of DM, represent a significant major unmet medical need. One mechanism that has been suggested for decades to cause pancreatic b cell dysfunction and diabetic end-organ damage is 'oxidative stress' (see Glossary), originally defined as an overproduction of reactive oxygen species (ROS). Antioxidants were considered the obvious therapeutic countermeasure but, clinically, have consistently disappointed [2]. Even worse, meta-analyses of clinical trials show that antioxidants may not only be ineffective, but harmful, and even increase mortality [2]. Recently, however, important conceptual breakthroughs in our understanding of ROS in general and DM in particular explain the failure of antioxidants and point towards entirely different mechanism-based and possibly curative therapeutic approaches. Our new understanding of ROS requires that many long-held misconceptions, such as the 'redox balance hypothesis' and the view that ROS are primarily stressors, disease triggers, and metabolic waste products, must be overcome. Instead, the many physiological roles of ROS and the existence of at least seven evolutionarily conserved ROS-producing enzymes (NOX1-5,

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GLP-1 Inhibits High-Glucose-Induced Oxidative Injury of Vascular Endothelial Cells

Cited by 53 publications

References 23 publications

<p>Hydrogen Sulfide Protects Against High Glucose-Induced Human Umbilical Vein Endothelial Cell Injury Through Activating PI3K/Akt/eNOS Pathway</p>

<p>Hydrogen Sulfide Protects Against High Glucose-Induced Human Umbilical Vein Endothelial Cell Injury Through Activating PI3K/Akt/eNOS Pathway</p>

A Genetic Polymorphism in the Pannexin1 Gene Predisposes for The Development of Endothelial Dysfunction with Increasing BMI

Reactive Oxygen Comes of Age: Mechanism-Based Therapy of Diabetic End-Organ Damage

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