Pretreatment with vildagliptin boosts ischemic-postconditioning effects on cardioprotection and expression profile of genes regulating autophagy and mitochondrial fission/fusion in diabetic heart with reperfusion injury
The burden of myocardial ischemia/reperfusion (IR) injury is 2–3-folds higher in diabetic patients, so protecting diabetic hearts is clinically important. Here, we investigated the effect of combinational therapy with vildagliptin and ischemic postconditioning (IPostC) on cardioprotection and the expression of genes regulating autophagy and mitochondrial function in diabetic hearts with IR injury. Type 2 diabetes was induced through high-fat diet and streptozotocin protocol in Wistar rats. Vildagliptin was orally administered to diabetic rats 5 weeks before IR injury. Myocardial-IR injury was modeled by ligation of left the coronary artery for 30 min followed by 60-min reperfusion, on a Langendorff-perfusion system. IPostC was applied at early reperfusion as 6 alternative cycles of 10-s reperfusion/ischemia. Creatine-kinase levels were measured spectrometrically, and infarct size was evaluated by TTC staining method. Left ventricles were harvested for assessing the expression levels of autophagy and mitochondrial-related genes using real-time PCR. Induction of diabetes significantly increased creatine-kinase release in comparison to healthy rats, and all treatments significantly reduced the release of enzyme toward control levels (P < 0.05). Only the combination therapy (IPostC + vildagliptin) could significantly reduce the infarct size of diabetic hearts as compared to untreated diabetic-IR group (P < 0.01). The levels of autophagy genes LC3 and p62 were significantly higher in diabetic groups than healthy ones. Induction of IR injury in diabetic hearts enhanced mitochondrial fission (drp-1) and reduced mitochondrial fusion (mfn1 and mfn2) genes. IPostC alone had no significant effect on the gene expression and vildagliptin alone could only affect LC3-II and mfn2 expressions. Nevertheless, administration of combination therapy significantly reduced the expression of both autophagy genes and increased both LC3-II/I and mfn2/1 ratios as compared with diabetic-IR hearts (P < 0.01–0.05). Application of this combination therapy could overcome the diabetes-induced failure of cardioprotection by individual treatments and improve mitochondrial dynamic and autophagy flux.
KeywordsCombination therapy Diabetes Cardioprotection Infarction Postconditioning Mitochondria Autophagy
The authors thank the Clinical Research Development Unit, Shohada Hospital and Molecular Medicine Research Center, Tabriz University of Medical Sciences for their kind supports.
VB and RB conceived and designed research. LP and RB conducted the experiments. LP, VB, and NP analyzed the data. LP, RB, and NP wrote the manuscript. All authors read and approved the manuscript.
This study was supported by a grant from National Elites Foundation, Tehran—Iran, and Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz—Iran.
Compliance with ethical standards
All animal procedures and experimental interventions were carried out in accordance with the ethical guidelines and approved by the local Ethical Committee for Animal Research.
Conflict of interest
The authors declare that they have no conflicts of interest.
- Apaijai N, Pintana H, Chattipakorn SC, Chattipakorn N (2013) Effects of vildagliptin versus sitagliptin, on cardiac function, heart rate variability and mitochondrial function in obese insulin-resistant rats. Br J Pharmacol 169(5):1048–1057. https://doi.org/10.1111/bph.12176 CrossRefPubMedPubMedCentralGoogle Scholar
- Apaijai N1, Chinda K, Palee S, Chattipakorn S, Chattipakorn N (2014) Combined vildagliptin and metformin exert better cardioprotection than monotherapy against ischemia-reperfusion injury in obese-insulin resistant rats. PLoS One 9(7):e102374. https://doi.org/10.1371/journal.pone.0102374 CrossRefPubMedPubMedCentralGoogle Scholar
- Badalzadeh R, Azimi A, Alihemmati A, Yousefi B (2017a) Chronic type-I diabetes could not impede the anti-inflammatory and antiapoptotic effects of combined postconditioning with ischemia and cyclosporine a in myocardial reperfusion injury. J Physiol Biochem 73(1):111–120. https://doi.org/10.1007/s13105-016-0530-4 CrossRefPubMedGoogle Scholar
- Badalzadeh R, Tabatabaei SM, Mohammadi M, Khaki A, Mohammadnezhad D (2017b) Combined postconditioning with ischemia and cyclosporine-A restore oxidative stress and histopathological changes in reperfusion injury of diabetic myocardium. Iran J Basic Med Sci 20(10):1079–1087. https://doi.org/10.22038/IJBMS.2017.9444 CrossRefPubMedPubMedCentralGoogle Scholar
- Bayrami G, Karimi P, Agha-Hosseini F, Feyzizadeh S, Badalzadeh R (2018) Effect of ischemic postconditioning on myocardial function and infarct size following reperfusion injury in diabetic rats pretreated with vildagliptin. J Cardiovasc Pharmacol Ther 23(2):174–183. https://doi.org/10.1177/1074248417729881 CrossRefPubMedGoogle Scholar
- Gottlieb RA, Mentzer RM Jr (2010) Autophagy during cardiac stress: joys and frustrations of autophagy. Annu Rev Physiol 72:45–59. https://doi.org/10.1146/annurev-physiol-021909-135757 CrossRefPubMedPubMedCentralGoogle Scholar
- Luc JGY, Choi JH, Rizvi SA, Phan K, MonchoEscrivà E, Patel S, Reeves GR, Boyle AJ, Entwistle JW, Morris RJ, Massey HT, Tchantchaleishvili V (2018) Percutaneous coronary intervention versus coronary artery bypass grafting in heart transplant recipients with coronary allograft vasculopathy: a systematic review and meta-analysis of 1,520 patients. Ann Cardiothorac Surg 7(1):19–30. https://doi.org/10.21037/acs.2018.01.10 CrossRefPubMedPubMedCentralGoogle Scholar
- Matsui Y, Takagi H, Qu X, Abdellatif M, Sakoda H, Asano T (2007) Distinct roles of autophagy in the heart during ischemia and reperfusion. Circ Res 100(6):914–922. https://doi.org/10.1161/01.RES.0000261924.76669.36 CrossRefPubMedGoogle Scholar
- Miyoshi T, Nakamura K, Yoshida M, Miura D, Oe H, Akagi S, Sugiyama H, Akazawa K, Yonezawa T, Wada J, Ito H (2014) Effect of vildagliptin, a dipeptidyl peptidase 4 inhibitor, on cardiac hypertrophy induced by chronic beta-adrenergic stimulation in rats. Cardiovasc Diabetol 13:43. https://doi.org/10.1186/1475-2840-13-43 CrossRefPubMedPubMedCentralGoogle Scholar
- Murase H, Kuno A, Miki T, Tanno M, Yano T, Kouzu H, Ishikawa S, Tobisawa T, Ogasawara M, Nishizawa K, Miura T (2015) Inhibition of DPP-4 reduces acute mortality after myocardial infarction with restoration of autophagic response in type 2 diabetic rats. Cardiovasc Diabetol 11(14):103. https://doi.org/10.1186/s12933-015-0264-6 CrossRefGoogle Scholar
- Oidor-Chan VH, Hong E, Pérez-Severiano F, Montes S, Torres-Narváez JC, Del Valle-Mondragón L, Pastelín-Hernández G, Sánchez-Mendoza A (2016) Fenofibrate plus metformin produces cardioprotection in a type 2 diabetes and acute myocardial infarction model. PPAR Res 8237264:1–14. https://doi.org/10.1155/2016/8237264 CrossRefGoogle Scholar
- Park SH, Nam JY, Han E, Lee YH, Lee BW, Kim BS, Cha BS, Kim CS, Kang ES (2016) Efficacy of different dipeptidyl peptidase-4 (DPP-4) inhibitors on metabolic parameters in patients with type 2 diabetes undergoing dialysis. Medicine(Baltimore) 95(32):e4543. https://doi.org/10.1097/MD.0000000000004543 CrossRefGoogle Scholar
- Xie J, Cui K, Hao H, Zhang Y, Lin H, Chen Z (2016) Acute hyperglycemia suppresses left ventricular diastolic function and inhibits autophagic flux in mice under prohypertrophic stimulation. Cardiovasc Diabetol 15(1):136. https://doi.org/10.1186/s12933-016-0452-z CrossRefPubMedPubMedCentralGoogle Scholar
- Yavari R, Badalzadeh R, Alipour MR, Tabatabaei SM (2016) Modulation of hippocampal gene expression of microRNA-146a/microRNA-155-nuclear factor-kappa B inflammatory signaling by troxerutin in healthy and diabetic rats. Indian J Pharm 48(6):675–680. https://doi.org/10.4103/0253-7613.194847 CrossRefGoogle Scholar
- Younis A, Eskenazi D, Goldkorn R, Leor J, Naftali-Shani N, Fisman EZ, Tenenbaum A, Goldenberg I, Klempfner R (2017) The addition of vildagliptin to metformin prevents the elevation of interleukin 1ß in patients with type 2 diabetes and coronary artery disease: a prospective, randomized, open-label study. Cardiovasc Diabetol 16(1):69. https://doi.org/10.1186/s12933-017-0551-5 CrossRefPubMedPubMedCentralGoogle Scholar
- Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP, Guyton RA, Vinten-Johansen J (2003) Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol 285(2):H579–H588. https://doi.org/10.1152/ajpheart.01064.2002 CrossRefPubMedGoogle Scholar