Acute canagliflozin treatment protects against in vivo myocardial ischemia–reperfusion injury in non-diabetic male rats and enhances endothelium-dependent vasorelaxation

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.

Autophagy stimulation and intracellular sodium reduction as mediators of the cardioprotective effect of sodium–glucose cotransporter 2 inhibitors

“…Experimental studies indicates that SGLT2 inhibitors can activate AMPK, SIRT1 and HIF‐1α in the myocardium, thereby potentially contributing to their actions to reduce heart failure and adverse renal events ( Figure ). Canagliflozin increases the expression, phosphorylation and activation of AMPK; although similar effects have been reported for empagliflozin and dapagliflozin, the evidence is less certain . Both canagliflozin and empagliflozin have been shown to upregulate SIRT1, and both empagliflozin and dapagliflozin induce the expression of HIF‐1α .…”

“…The overlap in the mechanism of action between metformin and SGLT2 inhibitors (with respect to AMPK activation) may explain why the magnitude of the benefit of SGLT2 inhibitors in large‐scale randomized controlled trials appears to be attenuated in patients receiving metformin, especially when it is used together with SGLT2 inhibitors that robustly activate AMPK (i.e. canagliflozin) . In the CANVAS trials, canagliflozin reduced the risk of cardiovascular death or hospitalization for heart failure by 36% in patients not receiving metformin, but by only 12% in those receiving metformin (interaction P = 0.03) .…”

Catechin relieves hypoxia/reoxygenation‐induced myocardial cell apoptosis via down‐regulating lncRNA MIAT

“…The establishment of MI/R rat model was conducted according to the previous report. 25 Thoracotomy was performed at the fourth intercostal space, then the pericardium was cut, and a 5-0 Prolene suture was placed around the left anterior descending coronary artery (LAD). The LAD was occluded for 30 minutes.…”

“…25 Thoracotomy was performed at the fourth intercostal space, then the pericardium was cut, and a 5-0 Prolene suture was placed around the left anterior descending coronary artery (LAD). We further found that catechin relieved H/Rinduced myocardial cell apoptosis through regulating CREB/MIAT/ Akt/Gsk-3β pathway, which might clarify the underlying mechanism of catechin in inhibiting H/R-induced myocardial cell apoptosis.…”

Antihyperglycemic drugs that improve cardiovascular outcomes and a model of diabetic cardiomyopathy

“…However, preclinical studies have revealed that SGLT2 inhibition does significantly reduce myocardial infarct size. [14][15][16] This is surprising: SGLT2 is not widely expressed in man, and there is negligible SGLT2 expression in the heart. 17 Remarkably, SGLT2i cardioprotection is independent of diabetic or glycemic status, and mediated through cytoprotective signaling: explanted hearts remain protected when perfused, ex vivo, following oral SGLTi administration.…”