Effect of DPP-4 inhibitor sitagliptin against ischemia-reperfusion (I/R) injury in hyperlipidemic animals

Authors

DOI:

https://doi.org/10.14232/abs.2018.2.180-189

Keywords:

dipeptidyl peptidase-4, DPP-4 inhibitors, hyperlipidemia, infarct size, ischemia-reperfusion injury, NOS, TRP channels

Abstract

Hyperlipidemia is a major risk factor associated with increased risk of myocardial infarction. Dipeptidyl peptidase-4 (DPP-4) inhibitors such as sitagliptin are a class of oral anti-diabetic drugs with secondary pleiotropic effects on metabolic and cardiovascular parameters. This study aimed to determine the possible cardioprotective effects of sitagliptin on ischemia-reperfusion (I/R) injury in animals kept on high-fat diet. Male Wistar rats were fed with high-fat diet (HF) for 12 weeks, to induce hyperlipidemia. During the last two weeks of the feeding period, animals were orally treated with different doses of sitagliptin (Sitg: 25, 50, 100, and 150 mg/kg/day), or saline as a control. Heart tissues were then isolated and subjected to two different I/R-injury protocols for infarct size (IS) measurement and biochemical analysis. To test the role of NOS enzyme, NOS inhibitor (L-NAME) was injected intraperitoneally for IS evaluation. As an effective dose, Sitg (50 mg) exhibited a significant impact on IS. NOS activity increased significantly in the Sitg (50 mg) treated groups; however this protective effect was abolished in the presence of L-NAME. The protective effect of Sitg that was mediated by TRP channels in our previous study on normolipidemic animals was abrogated in animals fed with high-fat diet.

Downloads

Download data is not yet available.

References

Al-Awar A, Almási N, Szabó R, Takacs I, Murlasits Z, Szűcs G, Török S, Pósa A, Varga C, Kupai K (2018) Novel potentials of the DPP-4 inhibitor sitagliptin against ischemia-reperfusion (I/R) injury in rat ex-vivo heart model. Int J Mol Sci 19(10):3226.

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.

Boughton-Smith NK, Evans SM, László F, Whittle BJ, Moncada S (1993) The induction of nitric oxide synthase and intestinal vascular permeability by endotoxin in the rat. Br J Pharmacol 110(3):1189-1195.

Ding M, Lei J, Han H, Li W, Qu Y, Fu E, Fu F, Wang X (2015) SIRT1 protects against myocardial ischemia-reperfusion injury via activating eNOS in diabetic rats. Cardiovasc Diabetol 14:143.

Downey JM, Cohen MV (2009) Why do we still not have cardioprotective drugs? Circulation 73(7):1171-1177.

Herman GA, Stevens C, Van Dyck K, Bergman A, Yi B, Smet M De, Snyder K, Hilliard D, Tanen M, Tanaka W, Wang AQ, Zeng W, Musson D, Winchell G, Davies MJ, Ramael S, Gottesdiener KM, Wagner JA (2005) Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clin Pharmacol Ther 78(6):675-688.

Jaarin K, Foong WD, Yeoh MH, Kamarul ZY, Qodriyah HM, Azman A, Zuhair JS, Juliana AH, Kamisah Y (2015) Mechanisms of the antihypertensive effects of Nigella sativa oil in L-NAME-induced hypertensive rats. Clinics (Sao Paulo) 70(11):751-757.

Kuo L, Davis MJ, Cannon MS, Chilian WM (1992) Pathophysiological consequences of atherosclerosis extend into the coronary microcirculation. Restoration of endothelium-dependent responses by L-arginine. Circ Res 70(3):465-476.

Kupai K, Csonka C, Fekete V, Odendaal L, van Rooyen J, Marais de W, Csont T, Ferdinandy P (2009) Cholesterol diet-induced hyperlipidemia impairs the cardioprotective effect of postconditioning: role of peroxynitrite. Am J Physiol Heart Circ Physiol 297(5):H1729-1735.

Lauzier B, Delemasure S, Pesant M, Collin B, Duvillard L, Vergely C, Connat JL, Rochette L (2009) A cholesterolrich diet improves resistance to ischemic insult in mouse hearts but suppresses the beneficial effect of post-conditioning. J Heart Lung Transplant 28(8):821-826.

Ma LL, Zhang FJ, Qian LB, Kong FJ, Sun JF, Zhou C, Peng YN, Xu HJ, Wang WN, Wen CY, Zhu MH, Chen G, Yu LN, Liu XB, Wang JA, Yan M (2013) Hypercholesterolemia blocked sevoflurane-induced cardioprotection against ischemia-reperfusion injury by alteration of the MG53/RISK/GSK3beta signaling. Int J Cardiol 168(4):3671-3678.

Nilius B, Droogmans G (2001) Ion channels and their functional role in vascular endothelium. Physiol Rev 81(4):1415-1459.

Nissen SE, Wolski K (2007) Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 356(24):2457-2471.

Onody A, Csonka C, Giricz Z, Ferdinandy P (2003) Hyperlipidemia induced by a cholesterol-rich diet leads to enhanced peroxynitrite formation in rat hearts. Cardiovasc Res 58(3):663-670.

Shenton FC, Pyner S (2014) Expression of transient receptor potential channels TRPC1 and TRPV4 in venoatrial endocardium of the rat heart. Neuroscience 267:195-204.

Shigematsu E, Yamakawa T, Kadonosono K, Terauchi Y (2014) Effect of sitagliptin on lipid profile in patients with type 2 diabetes mellitus. J Clin Med Res 6(5):327-335.

Torekov SS, Madsbad S, Holst JJ (2011) Obesity - an indication for GLP-1 treatment? Obesity pathophysiology and GLP-1 treatment potential. Obes Rev 12(8):593-601.

Vemula P, Gautam B, Abela G, Wang DH (2014) Myocardial ischemia/reperfusion injury: potential of TRPV1 agonists as cardioprotective agents. Cardiovasc Hematol Disord Drug Targ 14(1):71-78.

White CR, Brock TA, Chang LY, Crapo J, Briscoe P, Ku D, Bradley WA, Gianturco SH, Gore J, Freeman BA (1994) Superoxide and peroxynitrite in atherosclerosis. Proc Natl Acad Sci USA 91(3):1044-1048.

Wu NQ, Guo YL, Xu RX, Liu J, Zhu CG, Jiang LX, Li JJ (2013) Acute myocardial infarction in an 8-year old male child with homozygous familiar hypercholesterolemia: laboratory findings and response to lipid-lowering drugs. Clin Lab 59(7-8):901-907.

Wu Y, Tan X, Tian J, Liu X, Wang Y, Zhao H, Yan Z, Liu H, Ma X (2017) PPARγ agonist ameliorates the impaired fluidity of the myocardial cell membrane and cardiac injury in hypercholesterolemic rats. Cardiovasc Toxicol 17(1): 25-34.

Downloads

Published

2019-01-30

How to Cite

Al-awar, A., Almási, N., Szabó, R., Ménesi, R., Szűcs, G., Török, S., Pósa, A., Varga, C. and Kupai, K. (2019) “Effect of DPP-4 inhibitor sitagliptin against ischemia-reperfusion (I/R) injury in hyperlipidemic animals”, Acta Biologica Szegediensis, 62(2), pp. 180–189. doi: 10.14232/abs.2018.2.180-189.

Issue

Section

Articles

Most read articles by the same author(s)