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Cited by 117Nitric Oxide and Endothelin EffectsBlood Coagulation and Thrombosis MechanismsAdvanced Glycation End Products research

Hyperglycaemic Impairment of PAR2-Mediated Vasodilation: Prevention by Inhibition of Aortic Endothelial Sodium-Glucose-Co-Transporter-2 and Minimizing Oxidative Stress

El-Daly, Mahmoud, Pulakazhi Venu, Vivek Krishna, Saifeddine, Mahmoud, Mihara, Koichiro, Kang, Sean, Fedak, Paul W.M., Alston, Laurie A., Hirota, Simon A. +3 more·2018·Vascular Pharmacology
DOI 10.1016/j.vph.2018.06.006
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Abstract

Hyperglycaemia is a major contributor to diabetic cardiovascular disease with hyperglycaemia-induced endothelial dysfunction recognized as the initiating cause. Coagulation pathway-regulated proteinase-activated receptors (PARs) that can regulate vascular tone in vivo cause eNOS-mediated endothelium-dependent vasodilation; but, the impact of hyperglycaemia on this vasodilatory action of PAR stimulation and the signalling pathways involved are unknown. We hypothesized that vascular sodium-glucose co-transporter 2 activity and hyperglycaemia-induced oxidative stress involving Src-kinase, EGF receptor-kinase, Rho-kinase and protein-kinase-C biochemical signalling pathways would compromise PAR2-mediated endothelium-dependent vasodilation. Using an organ culture approach, wherein murine aorta rings were maintained for 24 h at hyperglycaemic 25 mM versus euglycaemic 10 mM glucose, we observed severely blunted acetylcholine/muscarinic and PAR2-mediated endothelial eNOS/NO-dependent vasodilation. PEG-catalase, superoxide-dismutase, and NADPH-oxidase inhibition (VAS2870) and either SGLT2-inhibition (canagliflozin/dapagliflozin/empagliflozin) or antioxidant gene induction (sulforaphane), prevented the hyperglycaemia-induced impairment of PAR2-mediated vasodilation. Similarly, inhibition of Src-kinase, EGF receptor-kinase, protein kinase-C and Rho-kinase also preserved PAR2-mediated vasodilation in tissues cultured under hyperglycaemic conditions. Thus, intracellular hyperglycaemia, that can be prevented with an inhibitor of the SGLT2 cotransporter that was identified in the vascular tissue and tissue-derived cultured endothelial cells by qPCR, western blot and immunohistochemistry, leads to oxidative stress that compromises PAR2-mediated NOS-dependent vasodilation by an NAPDH oxidase/reactive-oxygen-species-triggered signalling pathway involving EGFR/Src/Rho-kinase and PKC. The data point to novel antioxidant therapeutic strategies including use of an SGLT2 inhibitor and sulforaphane to mitigate hyperglycaemia-induced endothelial dysfunction.

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  • Metformin and other drugs used for T2DM, like SGLT2 inhibitors, may also reduce hyperglycemia-induced elevated endothelial ROS, independent of negative effects on complex 1, such as via inhibition of NADPH oxidase or blocking entry of glucose into the endothelium.

    “Metformin and other drugs used for T2DM, like the SGLT2 inhibitors, may also reduce hyperglycemia-induced elevated endothelial ROS, independent of negative effects on complex 1, such as via inhibition of NADPH oxidase or blocking the entry of glucose into the endothelium (32, 107–109, 187, 188)”

    From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [188]

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Authors
El-Daly, M., Pulakazhi Venu, V. K., Saifeddine, M., Mihara, K., Kang, S., Fedak, P. W. M., Alston, L. A., Hirota, S. A., Ding, H., Triggle, C. R., & Hollenberg, M. D.
Affiliations
  • University of Calgary (CA)
  • Weill Cornell Medical College in Qatar (QA)
Corresponding author
Hollenberg, Morley D.
ORCID
Venue
Vascular Pharmacology
Publisher
Elsevier BV
Published
2018-10
Volume
109
Pages
56-71
ISSN
1537-1891 (ISSN-L)
DOI
10.1016/j.vph.2018.06.006
OpenAlex
W2808400246
Cited by
117
References
78
Citations by year
2026: 5 · 2025: 12 · 2024: 11 · 2023: 14 · 2022: 16 · 2021: 26 · 2020: 15 · 2019: 14 · 2018: 3
FWCI
9.90
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Vascular Pharmacology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Canadian Institutes of Health Research
  • Qatar Foundation National Priorities Research Program (NPRP: 08165-3-054), 4-910-3-244)
Topics
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
Keywords
hyperglycemia, protease-activated receptor 2, endothelium-dependent vasodilation, endothelial dysfunction, SGLT2, SGLT2 inhibitors, oxidative stress, NADPH oxidase, reactive oxygen species, Src kinase, EGF receptor, Rho kinase, protein kinase C, sulforaphane, antioxidant therapy, diabetic cardiovascular disease, aortic endothelium
MeSH terms
Sodium-Glucose Transporter 2 Inhibitors, Animals, Antioxidants, Aorta, Dose-Response Relationship, Drug, Endothelium, Vascular, Hyperglycemia, Hypoglycemic Agents, Male, Mice, Inbred C57BL, Mitochondria, Nitric Oxide, Organ Culture Techniques, Protein Kinase C, Vasodilation, Signal Transduction, Oxidative Stress, src-Family Kinases, Endothelial Cells, Receptor, PAR-2, Sodium-Glucose Transporter 2, Nitric Oxide Synthase Type II, rho-Associated Kinases, ErbB Receptors

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