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Cardioprotection of Dapagliflozin and Vildagliptin in Rats with Cardiac Ischemia-Reperfusion Injury

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Cardioprotection of Dapagliflozin and Vildagliptin in Rats with Cardiac Ischemia-Reperfusion Injury 236 2 Journal of P Tanajak et al. Dapagliflozin and vildagliptin in 236:2 69–84 Endocrinology the heart RESEARCH Cardioprotection of dapagliflozin and vildagliptin in rats with cardiac ischemia-reperfusion injury Pongpan Tanajak1,2,3, Piangkwan Sa-nguanmoo1,2,3, Sivaporn Sivasinprasasn1, Savitree Thummasorn1,2,3, Natthaphat Siri-Angkul1,2,3, Siriporn C Chattipakorn1,3,4 and Nipon Chattipakorn1,2,3 1Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand 2Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand 3Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand 4Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand Correspondence should be addressed to N Chattipakorn: [email protected] Abstract Sodium-glucose cotransporter 2 inhibitor (SGLT2-i) effects on cardiac ischemia/ Key Words reperfusion (I/R) injury are unclear. Unlike SGLT2-i, dipeptidyl peptidase 4 inhibitors f SGLT2 inhibitors (DPP4-i) have shown effective cardioprotection in cardiac I/R injury. We aimed to f dapagliflozin investigate whether SGLT2-i reduces myocardial dysfunction and myocardial injury to f DPP4 inhibitors a greater extent than DPP4-i in obese insulin-resistant rats with/without cardiac I/R f vildagliptin injury. The high-fat (HF) diet-induced obese insulin-resistant rats were divided into 4 f cardioprotection groups and received the following treatments for 28 days: vehicle (HFV); vildagliptin at f pre-diabetes a dosage of 3 mg/kg/day (HFVil); dapagliflozin at a dosage of 1 mg/kg/day (HFDa) and f cardiac I/R injury combination drugs (HFDaVil). At the end, I/R injury was induced by a 30-min left anterior descending coronary occlusion and 120-min reperfusion. Dapagliflozin showed a greater efficacy than vildagliptin in improving the metabolic impairments, low frequency/high frequency (LF/HF) ratio, systolic blood pressure and left ventricular (LV) function in comparison to HFV rats. In cardiac I/R injury, dapagliflozin had a greater efficacy than vildagiptin in decreasing mitochondrial DRP1, cleaved caspase 3, LV dysfunction and infarct size in comparison to HFV rats. However, the combined therapy showed the greatest efficacy in attenuating LV dysfunction, mitochondrial DRP1 and infarct size in comparison to HFV rats. In conclusion, dapagliflozin has a more pronounced effect than vildagliptin in obese insulin-resistant rats for the improvement of LV function. In rats with cardiac I/R injury, although dapagliflozin had a greater efficacy on cardioprotection than vildagliptin, the combined therapy exerted the highest cardioprotective effects Journal of Endocrinology potentially by reducing mitochondrial fission. (2018) 236, 69–84 Introduction The sodium-glucose cotransporter 2 inhibitors (SGLT2-i) glucose excretion, thus improving glycemic control are a new class of anti-diabetic drugs, which exhibit a blood (Vrhovac et al. 2015). A recent clinical trial, EMPA-REG glucose-lowering effect by inhibiting glucose reabsorption OUTCOME, demonstrated that SGLT2-i empagliflozin at the proximal tubule of the nephron, resulting in reduced cardiovascular morbidity and mortality in decreased renal glucose reabsorption and increased renal patients with type 2 diabetes (T2DM) who are at a high risk http://joe.endocrinology-journals.org © 2018 Society for Endocrinology https://doi.org/10.1530/JOE-17-0457 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/25/2021 11:41:14PM via free access 10.1530/JOE-17-0457 Journal of P Tanajak et al. Dapagliflozin and vildagliptin in 236:2 70 Endocrinology the heart of cardiovascular events. Although the benefits of SGLT2-i Experimental animals are potentially through cardiometabolic regulation, this After 1 week of acclimatization, all rats were randomized effect of SGLT2-i in comparison with other anti-diabetic into 2 groups and were given either ND (n = 12) or HFD drugs, especially in pre-diabetic conditions both with and (n = 48) for 12 weeks. At week 12, ND rats were fed without myocardial ischemia/reperfusion (I/R) injury, continuously with ND and vehicle (NDV) for 28 days. At as well as its underlying mechanism have never been week 12, HFD rats were subdivided into 4 experimental investigated. groups (n = 12/group), and each group received one of Incretin-based therapy using dipeptidyl peptidase the following treatments via oral gavage feeding for 4 inhibitors (DPP4-i) is a well-known effective glycemic 28 days: (1) HFD rats received vehicle (HFV); (2) HFD rats control remedy. The cardioprotective effects of DPP4-i received vildagliptin 3 mg/kg/day (HFVil); (3) HFD rats beyond its glycemic regulating effects have been received dapagliflozin 1 mg/kg/day (HFDa) or (4) HFD reported to lead to an improvement in cardiac function rats received the combination of vildagliptin 3 mg/kg/ in high-fat diet (HFD)-induced pre-diabetes rat models day and dapagliflozin 1 mg/kg/day (HFDaVil). At the end (Apaijai et al. 2013, Tanajak et al. 2017). Treatment with of week 12 of the assigned diet treatment and again after DPP4-i provided effective cardioprotection in rats with 28 days of drug treatments, the metabolic parameters, blood myocardial I/R injury (Chinda et al. 2014). In healthy chemistry, 24-h urine volume, urinary glucose excretion volunteers, treatment with vildagliptin at the highest (UGE), 24-h UGE, blood pressure and HRV were investigated. daily therapeutic dose or a fourfold higher dose did not Then, in vivo myocardial I/R were induced by left anterior change the QT interval, nor did it have adverse effects on descending (LAD) coronary artery ligation for 30 min cardiac conduction (He et al. 2011). However, the benefit followed by reperfusion for 120 min. During the myocardial of its glycemic control as well as cardioprotection in obese I/R procedure, lead II ECG was used to record arrhythmia insulin-resistant with cardiac I/R injury compared to parameter measurements. LV function was determined SGLT2-i is not known. using a pressure–volume (P–V) loop at the beginning of This study aimed to investigate the effects of SGLT2-i the I/R procedure (baseline) and throughout the cardiac I/R (dapaglipflozin), DPP4-i (vildagliptin) and a combined study. At the end of the cardiac I/R procedure, the heart was therapy of both agents on metabolic regulation, blood removed rapidly and then perfused with 20 mL cold 0.9% chemistry, blood pressure, heart rate variability (HRV) NSS. Finally, the removed hearts were used to assess the levels and LV function in HFD- induced pre-diabetic rats. of myocardial infarction, cardiac mitochondrial function Moreover, the therapeutic effects of these drugs on cardiac and protein expression. The myocardium was divided into arrhythmia, myocardial infarction size and LV function, as the remote area and ischemic area for measurements of well as the underlying mechanisms under cardiac I/R injury cardiac mitochondrial function, cardiac lipid peroxidation, were investigated in HFD-induced obese insulin-resistant tissue proteins expression, mitochondrial protein expression rats. Our hypothesis is that dapaglipflozin provides more and myocardial infarction area. The experimental design, effective metabolic regulation and cardioprotection than the number of rats and the details of data sets for analysis vildagliptin in HFD-induced obese insulin-resistant rats, are listed in Fig. 1. both with/without cardiac I/R injury and also that the combined therapy exerts superior cardioprotection in these rats, when compared with single regimens. Myocardial I/R surgical procedure Rats were anesthetized by an intramuscular injection of Zoletil (zolazepam and tiletamine) 50 mg/kg in Materials and methods combination with xylazine 3 mg/kg and were ventilated via a tracheotomy tube by Harvard Rodent Ventilator Model Ethical approval 683 (Harvard Apparatus, Holliston, MA, USA) (Pongkan All experimental protocols in this study were approved et al. 2016). Lead II ECG was monitored continuously by the Faculty of Medicine, Chiang Mai University throughout the entire I/R procedure. A left intercostal Institutional Animal Care and Use Committee (Permit thoracotomy incision was performed, and then the LAD No. 46/2558), in compliance with NIH guidelines and coronary artery was identified and ligated at approximately in accordance with the ARRIVE guidelines for reporting 2 mm distal to the origin of the left coronary, by a 5-0 experiments involving animals (Kilkenny et al. 2010). silk suture to induce myocardial infarction. The LAD was http://joe.endocrinology-journals.org © 2018 Society for Endocrinology https://doi.org/10.1530/JOE-17-0457 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/25/2021 11:41:14PM via free access Research Journal of P Tanajak et al. Dapagliflozin and vildagliptin in 236:2 71 Endocrinology the heart Figure 1 Diagram of the experimental protocol, number of animals and data set for analysis of this study. HFD, high-fat diet; HFDa, high-fat diet treated with dapagliflozin; HFDaVil, high-fat diet treated with vildagliptin and dapagliflozin; HFV, high-fat diet treated with vehicle; HFVil, high-fat diet treated with vildagliptin; HPLC, high-performance liquid chromatography; MMP, mitochondrial membrane potential; ND, normal diet; NDV, normal diet treated with vehicle; ROS,
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