eprintid: 26360
rev_number: 13
eprint_status: archive
userid: 1589
dir: disk0/00/02/63/60
datestamp: 2019-06-18 12:59:43
lastmod: 2019-07-11 11:49:09
status_changed: 2019-06-18 12:59:43
type: article
metadata_visibility: show
creators_name: Sayour, Alex Ali
creators_name: Korkmaz‑Icöz, Sevil
creators_name: Loganathan, Sivakkanan
creators_name: Ruppert, Mihály
creators_name: Sayour, Viktor Nabil
creators_name: Oláh, Attila
creators_name: Benke, Kálmán
creators_name: Brune, Maik
creators_name: Benkő, Rita
creators_name: Horváth, Eszter Mária
creators_name: Karck, Matthias
creators_name: Merkely, Béla
creators_name: Radovits, Tamás
creators_name: Szabó, Gábor
title: Acute canagliflozin treatment protects against in vivo myocardial ischemia-reperfusion injury in non-diabetic male rats and enhances endothelium-dependent vasorelaxation
subjects: 610
divisions: 910100
divisions: 910200
keywords: Sodium–glucose cotransporter-2 inhibitor, Canagliflozin, Myocardial ischemia–reperfusion injury, Cardioprotection
abstract: Background: The sodium–glucose cotransporter-2 (SGLT2) inhibitor canagliflozin has been shown to reduce major cardiovascular events in type 2 diabetic patients, with a pronounced decrease in hospitalization for heart failure (HF) especially in those with HF at baseline. These might indicate a potent direct cardioprotective effect, which is currently incompletely understood. We sought to characterize the cardiovascular effects of acute canagliflozin treatment in healthy and infarcted rat hearts.

Methods: Non-diabetic male rats were subjected to sham operation or coronary artery occlusion for 30 min, followed by 120 min reperfusion in vivo. Vehicle or canagliflozin (3 µg/kg bodyweight) was administered as an intravenous bolus 5 min after the onset of ischemia. Rats underwent either infarct size determination with serum troponin-T measurement, or functional assessment using left ventricular (LV) pressure–volume analysis. Protein, mRNA expressions, and 4-hydroxynonenal (HNE) content of myocardial samples from sham-operated and infarcted rats were investigated. In vitro organ bath experiments with aortic rings from healthy rats were performed to characterize a possible effect of canagliflozin on vascular function.   

Results: Acute treatment with canagliflozin significantly reduced myocardial infarct size compared to vehicle (42.5 ± 2.9% vs. 59.3 ± 4.2%, P = 0.006), as well as serum troponin-T levels. Canagliflozin therapy alleviated LV systolic and diastolic dysfunction following myocardial ischemia–reperfusion injury (IRI), and preserved LV mechanoenergetics. Western blot analysis revealed an increased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and endothelial nitric-oxide synthase (eNOS), which were not disease-specific effects. Canagliflozin elevated the phosphorylation of Akt only in infarcted hearts. Furthermore, canagliflozin reduced the expression of apoptotic markers (Bax/Bcl-2 ratio) and that of genes related to myocardial nitro-oxidative stress. In addition, treated hearts showed significantly lower HNE positivity. Organ bath experiments with aortic rings revealed that preincubation with canagliflozin significantly enhanced endothelium-dependent vasodilation in vitro, which might explain the slight LV afterload reducing effect of canagliflozin in healthy rats in vivo.

Conclusions: Acute intravenous administration of canagliflozin after the onset of ischemia protects against myocardial IRI. The medication enhances endothelium dependent vasodilation independently of antidiabetic action. These findings might further contribute to our understanding of the cardiovascular protective effects of canagliflozin reported in clinical trials.
date: 2019
publisher: BioMed Central
id_scheme: DOI
ppn_swb: 1668938111
own_urn: urn:nbn:de:bsz:16-heidok-263605
language: eng
bibsort: SAYOURALEXACUTECANAG2019
full_text_status: public
publication: Journal of translational medicine
volume: 17
number: 127
place_of_pub: London
pagerange: 1-14
issn: 1479-5876
citation:   Sayour, Alex Ali ; Korkmaz‑Icöz, Sevil ; Loganathan, Sivakkanan ; Ruppert, Mihály ; Sayour, Viktor Nabil ; Oláh, Attila ; Benke, Kálmán ; Brune, Maik ; Benkő, Rita ; Horváth, Eszter Mária ; Karck, Matthias ; Merkely, Béla ; Radovits, Tamás ; Szabó, Gábor  (2019) Acute canagliflozin treatment protects against in vivo myocardial ischemia-reperfusion injury in non-diabetic male rats and enhances endothelium-dependent vasorelaxation.  Journal of translational medicine, 17 (127).  pp. 1-14.  ISSN 1479-5876     
document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/26360/1/12967_2019_Article_1881.pdf