ISSN 2996-8215
International Journal of Cardiology | Vol. 6, No. 4, April 2015 | pp. 25–32
DOI: 10.46882/2015/IJC/000073
Original Research Article
Cardioprotective Effects of Sotagliflozin in a Rat Model of Ischemia-Reperfusion Injury: Modulation of Myocardial SGLT1 Pathways
Kenji Tanaka¹, Satoshi Yamada¹, Takashi Sato²
¹Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
²Division of Metabolic Diseases, Tokyo Medical and Dental University, Tokyo, Japan
Abstract:
Sotagliflozin is a dual sodium-glucose cotransporter 1 and 2 (SGLT1/2) inhibitor that improves clinical endpoints in heart failure. Unlike SGLT2, SGLT1 is expressed directly within human and rodent myocardium, meaning dual inhibition might provide unique cellular protections during ischemic shocks. This study evaluated the direct cardioprotective effects of sotagliflozin against myocardial ischemia-reperfusion (I/R) injury in rats and explored the role of downstream sodium-hydrogen exchanger-1 (NHE-1) pathing. Adult male Sprague-Dawley rats were randomized into three groups (n = 12 per group): Sham, I/R control, and Sotagliflozin + I/R. Ischemia was induced by occluding the left anterior descending coronary artery for 30 minutes, followed by 120 minutes of reperfusion. Sotagliflozin (10 mg/kg/day) was administered via oral gavage for 14 days prior to I/R. Pretreatment with sotagliflozin significantly limited myocardial infarct size compared to the I/R control cohort (26.4% ± 3.2% vs. 42.6% ± 4.1%, p < 0.01). Sotagliflozin administration also preserved left ventricular developed pressure and limited the post-ischemic rise in serum creatine kinase-MB and lactate dehydrogenase values (p < 0.05). Western blot and biochemical analyses revealed that sotagliflozin significantly suppressed intracellular sodium overload and down-regulated myocardial NHE-1 expression, reducing cytosolic calcium overload and cleavage of pro-apoptotic caspase-3 pathways. Sotagliflozin exerts potent cardioprotective effects against myocardial ischemia-reperfusion injury in rats, reducing cardiomyocyte death by down-regulating NHE-1 pathways and cellular ionic loading via localized SGLT1 modulation.
Keywords: Ischemia-reperfusion injury, Sotagliflozin, SGLT1 inhibitors, Sodium-hydrogen exchanger-1, Apoptosis, Infarct size
Received: January 08, 2015; Revised: February 20, 2015; Accepted: March 12, 2015; Published: April 22, 2015