Acute canagliflozin treatment protects against myocardial ischemia-reperfusion injury in a rat model
█ Original article
Sayour Alex Ali1,2, Ruppert Mihály1,2, Oláh Attila1, Benke Kálmán1, Benkő Rita3, Horváth Eszter Mária3, Korkmaz-Icöz Sevil2, Loganathan Sivakkanan2, Karck Matthias2, Merkely Béla1, Szabó Gábor2, Radovits Tamás1
1Semmelweis Egyetem, Városmajori Szív- és Érgyógyászati Klinika, Budapest
2Ruprecht-Karls Egyetem, Szívsebészeti Klinika, Heidelberg, Németország
3Semmelweis Egyetem, Élettani Intézet, Budapest
Introduction: The sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin reduces major cardiovascular events in patients with type 2 diabetes. This suggests that there is a direct cardioprotective effect, which is incompletely understood. We aimed to characterize the cardiovascular effects of canagliflozin in a rat model of myocardial ischemia-reperfusion injury.
Methods: Non-diabetic rats underwent sham operation or left anterior descending coronary artery occlusion for 30 minutes, followed by 120 minutes of reperfusion. Vehicle or canagliflozin was administered as a single intravenous bolus in the 5th minute of ischemia. We measured infarct size, serum troponin T and left ventricular (LV) function. Protein and mRNA expression, as well as immunohistochemical measurements were carried out on LV myocardial samples. We investigated the vascular effect of canagliflozin with in vitro myograph experiments.
Results: Acute treatment with canagliflozin reduced myocardial infarct size (42.5±2.9% vs. 59.3±4.2%, P=0.006) and serum troponin T levels compared to vehicle treatment. Canagliflozin alleviated myocardial ischemia-reperfusion (IR) injury-associated LV systolic and diastolic dysfunction. The treatment increased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK), Akt and endothelial nitric-oxide synthase (eNOS), while reduced the myocardial expression of apoptotic (Bax/Bcl-2 ratio) and oxidative stress-related genes. Lipid peroxidation decreased in treated hearts. Preincubation with canagliflozin enhanced endothelium-dependent vasorelaxation.
Conclusions: Intravenously administered SGLT2 inhibitor canagliflozin reduces myocardial IR injury independently of antidiabetic action and enhances endothelium-dependent vasorelaxation. Our results might contribute to the understanding of the possible direct cardioprotective effect of canagliflozin seen in clinical trials.