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

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

  • Vascul Pharmacol. 2018 Oct;109:56-71. doi: 10.1016/j.vph.2018.06.006.
Mahmoud El-Daly 1 Vivek Krishna Pulakazhi Venu 2 Mahmoud Saifeddine 2 Koichiro Mihara 2 Sean Kang 3 Paul W M Fedak 3 Laurie A Alston 2 Simon A Hirota 2 Hong Ding 4 Chris R Triggle 5 Morley D Hollenberg 6
Affiliations

Affiliations

  • 1 Inflammation Research Network-Snyder Institute for Chronic Disease, University of Calgary Cumming School of Medicine, Calgary, AB T2N 4N1, Canada; Department of Pharmacology & Toxicology, Faculty of Pharmacy, Minia University, Minia, Egypt.
  • 2 Inflammation Research Network-Snyder Institute for Chronic Disease, University of Calgary Cumming School of Medicine, Calgary, AB T2N 4N1, Canada; Department of Physiology & Pharmacology, University of Calgary Cumming School of Medicine, Calgary, AB T2N 4N1, Canada.
  • 3 Section of Cardiac Surgery, Department of Cardiac Science, Libin Cardiovascular Institute, University of Calgary Cumming School of Medicine, Calgary, AB T2N 4N1, Canada.
  • 4 Departments of Pharmacology and Medical Education, Weill Cornell Medicine in Qatar, Ar-Rayyan, Qatar.
  • 5 Department of Physiology & Pharmacology, University of Calgary Cumming School of Medicine, Calgary, AB T2N 4N1, Canada; Departments of Pharmacology and Medical Education, Weill Cornell Medicine in Qatar, Ar-Rayyan, Qatar.
  • 6 Inflammation Research Network-Snyder Institute for Chronic Disease, University of Calgary Cumming School of Medicine, Calgary, AB T2N 4N1, Canada; Department of Physiology & Pharmacology, University of Calgary Cumming School of Medicine, Calgary, AB T2N 4N1, Canada; Department of Medicine, University of Calgary Cumming School of Medicine, Calgary, AB T2N 4N1, Canada. Electronic address: [email protected].
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.

Keywords

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

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