Hyperglycaemic impairment of PAR2-mediated vasodilation: Prevention by inhibition of aortic endothelial sodium-glucose-co-Transporter-2 and minimizing oxidative stress

Mahmoud El-Daly, Vivek Krishna Pulakazhi Venu, Mahmoud Saifeddine, Koichiro Mihara, Sean Kang, Paul W.M. Fedak, Laurie A. Alston, Simon A. Hirota, Hong Ding, Christopher Triggle, Morley D. Hollenberg

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish
JournalVascular Pharmacology
DOIs
Publication statusAccepted/In press - 1 Jan 2018

Fingerprint

Sodium-Glucose Transporter 2
Symporters
Vasodilation
Hyperglycemia
Oxidative Stress
rho-Associated Kinases
src-Family Kinases
Proteinase-Activated Receptors
Blood Vessels
Epidermal Growth Factor Receptor
Endothelium
Antioxidants
NADPH Oxidase
Organ Culture Techniques
Protein Kinase C
Cholinergic Agents
Acetylcholine
Superoxide Dismutase
Aorta
Cultured Cells

Keywords

  • Hyperglycaemia
  • Oxidative vascular dysfunction
  • Proteinase-activated receptor-2
  • SGLT2 inhibitor
  • Sulforaphane

ASJC Scopus subject areas

  • Physiology
  • Molecular Medicine
  • Pharmacology

Cite this

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.; Ding, Hong; Triggle, Christopher; Hollenberg, Morley D.

In: Vascular Pharmacology, 01.01.2018.

Research output: Contribution to journalArticle

El-Daly, Mahmoud ; Pulakazhi Venu, Vivek Krishna ; Saifeddine, Mahmoud ; Mihara, Koichiro ; Kang, Sean ; Fedak, Paul W.M. ; Alston, Laurie A. ; Hirota, Simon A. ; Ding, Hong ; Triggle, Christopher ; Hollenberg, Morley D. / Hyperglycaemic impairment of PAR2-mediated vasodilation : Prevention by inhibition of aortic endothelial sodium-glucose-co-Transporter-2 and minimizing oxidative stress. In: Vascular Pharmacology. 2018.
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AU - Pulakazhi Venu, Vivek Krishna

AU - Saifeddine, Mahmoud

AU - Mihara, Koichiro

AU - Kang, Sean

AU - Fedak, Paul W.M.

AU - Alston, Laurie A.

AU - Hirota, Simon A.

AU - Ding, Hong

AU - Triggle, Christopher

AU - Hollenberg, Morley D.

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N2 - 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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