Abstract
The mechanism by which SGLT2 inhibitors reduce cardiac events in diabetic patients remains unclear. Here, we examined the effects of an SGLT2 inhibitor on the acute survival rate after myocardial infarction (MI) in an animal model of type 2 diabetes mellitus (DM) and the possible involvement of modification of cardiac metabolomes and antioxidative proteins. MI was induced in DM Otsuka Long-Evans Tokushima Fatty (OLETF) rats and Long-Evans Tokushima Otsuka (LETO) control rats. Treatment with empagliflozin (10 mg/kg per day, 14 days) before MI reduced blood glucose and increased blood and myocardial β-hydroxybutyrate (βOHB) levels in OLETF. Survival rate at 48 hours after MI was significantly lower in OLETF rats than in LETO rats (40% vs. 84%), and empagliflozin significantly improved the survival rate in OLETF rats to 70%, although the sizes of MI were comparable. Patterns of metabolomes and gene expression in the noninfarcted myocardium of OLETF rats were consistent with increased fatty acid oxidation and decreased glucose oxidation. The patterns were modified by empagliflozin, suggesting both increased glucose oxidation and ketone utilization in OLETF rats. Empagliflozin prevented reduction of ATP level in the noninfarcted myocardium after MI and significantly increased myocardial levels of Sirt3 and superoxide dismutase 2 in OLETF rats. Administration of βOHB partially mimicked the effects of empagliflozin in OLETF rats. The results suggest that empagliflozin prevents DM-induced increase in post-MI mortality, possibly by protective modification of cardiac energy metabolism and antioxidant proteins.
Footnotes
- Received September 14, 2018.
- Accepted December 10, 2018.
H.O. and Ta.M. equally contributed to this study.
This study was supported by a grant from Boehringer Ingelheim, and a Research and Education Grant 2016-2017 from Sapporo Medical University.
Boehringer Ingelheim did not play any role in the collection, analysis, and interpretation of data or the writing of the manuscript.
Part of this work was presented at the annual meeting of the European Association for the Study of Diabetes, Lisbon, Portugal, September 11–15, 2017.
↵This article has supplemental material available at jpet.aspetjournals.org.
- Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics