Empagliflozin limits myocardial infarction in vivo and cell death in vitro: Role of STAT3, mitochondria, and redox aspects

Frontiers in Physiology

Volumn 8, Issue DEC, 2017, Pages

  Andreadou, Ioanna ^a   Efentakis, Panagiotis ^a   Balafas, Evangelos ^b   Togliatto, Gabriele ^c   Davos, Constantinos H ^d   Varela, Aimilia ^d   Dimitriou, Constantinos A ^d   Nikolaou, Panagiota Efstathia ^a   Maratou, Eirini ^e   Lambadiari, Vaia ^f   Ikonomidis, Ignatios ^g   Kostomitsopoulos, Nikolaos ^b   Brizzi, Maria F ^c   Dimitriadis, George ^f   Iliodromitis, Efstathios K ^g  

^a NATIONAL AND KAPODISTRIAN UNIVERSITY OF ATHENS   (Greece)

^b Academy of Athens Biomedical Research Foundation   (Greece)

^c UNIVERSITY OF TURIN   (Italy)

^d BIOMEDICAL RESEARCH FOUNDATION   (Greece)

^e Hellenic National Center for the Research   (Greece)

^f UNIVERSITY OF ATHENS   (Greece)

^g UNIVERSITY OF ATHENS MEDICAL SCHOOL   (Greece)

Author keywords

Cardiac function; Cardioprotection; Empagliflozin; Infarct size; Molecular signaling; STAT3 pathway

Indexed keywords

ADENOSINE TRIPHOSPHATE; ADVANCED GLYCATION END PRODUCT; CALCIUM; CHOLESTEROL; EMPAGLIFLOZIN; GLUCOSE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE ALPHA; INDUCIBLE NITRIC OXIDE SYNTHASE; INTERLEUKIN 6; MALONALDEHYDE; STAT3 PROTEIN; TRIACYLGLYCEROL; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIINFLAMMATORY ACTIVITY; ANTIOXIDANT ACTIVITY; ARTICLE; CALCIUM RETENTION CAPACITY; CARDIOVASCULAR PARAMETERS; CELL DEATH; CELL HYPOXIA; CELL SURVIVAL; CELL VIABILITY; CHOLESTEROL BLOOD LEVEL; CONTROLLED STUDY; DRUG EFFICACY; DRUG MECHANISM; ENDOTHELIUM CELL; GLUCOSE BLOOD LEVEL; H9C2(2-1) CELL LINE; HEART FUNCTION; HEART INFARCTION; HEART INFARCTION SIZE; HEART LEFT VENTRICLE FRACTIONAL SHORTENING; HEART MITOCHONDRION; HEART MUSCLE BIOPSY; HEART MUSCLE ISCHEMIA; HEART MUSCLE REPERFUSION; HEART PROTECTION; IN VITRO STUDY; IN VIVO STUDY; LIPID PEROXIDATION; MALE; MEAN ARTERIAL PRESSURE; MITOCHONDRIAL PERMEABILITY; MOUSE; NONHUMAN; OXIDATION REDUCTION STATE; PROTEIN ANALYSIS; PROTEIN EXPRESSION; PROTEIN FUNCTION; SIGNAL TRANSDUCTION; TREATMENT DURATION; TRIACYLGLYCEROL BLOOD LEVEL; WEIGHT REDUCTION; WESTERN DIET;

EID: 85038408228     PISSN: None     EISSN: 1664042X     Source Type: Journal    
DOI: 10.3389/fphys.2017.01077     Document Type: Article

References (37)

1. Andreadou, I., Bibli, S. I., Mastromanolis, E., Zoga, A., Efentakis, P., Papaioannou, N., et al. (2015). Transient carotid ischemia as a remote conditioning stimulus for myocardial protection in anesthetized rabbits: insights into intracellular signaling. Int. J. Cardiol. 184, 140-151. doi: 10.1016/j.ijcard.2015.01.079
2. Andreadou, I., Farmakis, D., Prokovas, E., Sigala, F., Zoga, A., Spyridaki, K., et al. (2012). Short-term statin administration in hypercholesterolemic rabbits resistant to postconditioning: effects on infarct size, endothelial nitric oxide synthase and nitro-oxidative stress. Cardiovasc. Res. 94, 501-509. doi: 10.1093/cvr/cvs121
3. Andreadou, I., Iliodromitis, E. K., Mikros, E., Bofilis, E., Zoga, A., Constantinou, M., et al. (2004). Melatonin does not prevent the protection of ischemic preconditioning in vivo despite its antioxidant effect against oxidative stress. Free Radic. Biol. Med. 37, 500-510. doi: 10.1016/j.freeradbiomed.2004.05.005
4. Baartscheer, A., Schumacher, C. A., Wust, R. C., Fiolet, J. W., Stienen, G. J., Coronel, R., et al. (2017). Empagliflozin decreases myocardial cytoplasmic Na+ through inhibition of the cardiac Na+/H+ exchanger in rats and rabbits. Diabetologia 60, 568-573. doi: 10.1007/s00125-016-4134-x
5. Baldanzi, G., Filigheddu, N., Cutrupi, S., Catapano, F., Bonissoni, S., Fubini, A., et al. (2002). Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKT. J. Cell Biol. 159, 1029-1037. doi: 10.1083/jcb.200207165
6. Bernardi, P., and Di Lisa, F. (2015). The mitochondrial permeability transition pore: molecular nature and role as a target in cardioprotection. J. Mol. Cell. Cardiol. 78, 100-106. doi: 10.1016/j.yjmcc.2014.09.023
7. Bibli, S. I., Andreadou, I., Chatzianastasiou, A., Tzimas, C., Sanoudou, D., Kranias, E., et al. (2015). Cardioprotection by H2S engages a cGMP-dependent protein kinase G/phospholamban pathway. Cardiovasc. Res. 106, 432-442. doi: 10.1093/cvr/cvv129
8. Bibli, S. I., Andreadou, I., Glynos, C., Chatzianastasiou, A., Toumpanakis, D., Zakynthinos, S. G., et al. (2016). Exposure to cigarette smoke abrogates the beneficial effect of ischemic postconditioning. Am. J. Physiol. Heart Circ. Physiol. 311, H1321-H1332. doi: 10.1152/ajpheart.00925.2015
9. Calvert, J. W., Gundewar, S., Jha, S., Greer, J. J., Bestermann, W. H., Tian, R., et al. (2008). Acute metformin therapy confers cardioprotection against myocardial infarction via AMPK-eNOS-mediated signaling. Diabetes 57, 696-705. doi: 10.2337/db07-1098
10. Chatzianastasiou, A., Bibli, S. I., Andreadou, I., Efentakis, P., Kaludercic, N., Wood, M. E., et al. (2016). Cardioprotection by H2S donors: nitric oxide-dependent and independent mechanisms. J. Pharmacol. Exp. Ther. 358, 431-440. doi: 10.1124/jpet.116.235119
11. Chen, J., Fan, F., Wang, J. Y., Long, Y., Gao, C. L., Stanton, R. C., et al. (2017). The efficacy and safety of SGLT2 inhibitors for adjunctive treatment of type 1 diabetes: a systematic review and meta-analysis. Sci. Rep. 7:44128. doi: 10.1038/srep44128
12. Cheng, S. T., Chen, L., Li, S. Y., Mayoux, E., and Leung, P. S. (2016). The effects of empagliflozin, an SGLT2 inhibitor, on pancreatic beta-cell mass and glucose homeostasis in type 1 diabetes. PLoS ONE 11:e0147391. doi: 10.1371/journal.pone.0147391
13. Fitchett, D., Zinman, B., Wanner, C., Lachin, J. M., Hantel, S., Salsali, A., et al. (2016). Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME(R) trial. Eur. Heart J. 37, 1526-1534. doi: 10.1093/eurheartj/ehv728
14. Gordon, J. W., Shaw, J. A., and Kirshenbaum, L. A. (2011). Multiple facets of NF-κB in the heart: to be or not to NF-κB. Circ. Res. 108, 1122-1132. doi: 10.1161/CIRCRESAHA.110.226928
15. Habibi, J., Aroor, A. R., Sowers, J. R., Jia, G., Hayden, M. R., Garro, M., et al. (2017). Sodium glucose transporter 2 (SGLT2) inhibition with empagliflozin improves cardiac diastolic function in a female rodent model of diabetes. Cardiovasc. Diabetol. 16:9. doi: 10.1186/s12933-016-0489-z
16. Hausenloy, D. J., Barrabes, J. A., Bøtker, H. E., Davidson, S. M., Di Lisa, F., Downey, J., et al. (2016). Ischaemic conditioning and targeting reperfusion injury: a 30 year voyage of discovery. Basic Res. Cardiol. 111:70. doi: 10.1007/s00395-016-0588-8
17. Hawley, S. A., Ford, R. J., Smith, B. K., Gowans, G. J., Mancini, S. J., Pitt, R. D., et al. (2016). The Na+/glucose cotransporter inhibitor canagliflozin activates AMPK by inhibiting mitochondrial function and increasing cellular AMP levels. Diabetes 65, 2784-2794. doi: 10.2337/db16-0058
18. Heusch, G. (2015). Molecular basis of cardioprotection: signal transduction in ischemic pre-, post-, and remote conditioning. Circ. Res. 116, 674-699. doi: 10.1161/CIRCRESAHA.116.305348
19. Kleinbongard, P., Skyschally, A., Gent, S., Pesch, M., and Heusch, G. (2017). STAT3 as a common signal of ischemic conditioning: a lesson on 'rigor and reproducibility' in preclinical studies on cardioprotection. Basic Res. Cardiol. 113, 3. doi: 10.1007/s00395-017-0660-z
20. Lee, T. M., Chang, N. C., and Lin, S. Z. (2017). Dapagliflozin, a selective SGLT2 inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts. Free Radic. Biol. Med. 104, 298-310. doi: 10.1016/j.freeradbiomed.2017.01.035
21. Miki, T., Itoh, T., Sunaga, D., and Miura, T. (2012). Effects of diabetes on myocardial infarct size and cardioprotection by preconditioning and postconditioning. Cardiovasc. Diabetol. 11:67. doi: 10.1186/1475-2840-11-67
22. Oelze, M., Kroller-Schon, S., Welschof, P., Jansen, T., Hausding, M., Mikhed, Y., et al. (2014). The sodium-glucose co-transporter 2 inhibitor empagliflozin improves diabetes-induced vascular dysfunction in the streptozotocin diabetes rat model by interfering with oxidative stress and glucotoxicity. PLoS ONE 9:e112394. doi: 10.1371/journal.pone.0112394
23. Pagliaro, P., and Penna, C. (2015). Redox signalling and cardioprotection: translatability and mechanism. Br. J. Pharmacol. 172, 1974-1995. doi: 10.1111/bph.12975
24. Panchapakesan, U., Pegg, K., Gross, S., Komala, M. G., Mudaliar, H., Forbes, J., et al. (2013). Effects of SGLT2 inhibition in human kidney proximal tubular cells-renoprotection in diabetic nephropathy? PLoS ONE 8:e54442. doi: 10.1371/journal.pone.0054442
25. Papathanasiou, S., Rickelt, S., Soriano, M. E., Schips, T. G., Maier, H. J., Davos, C. H., et al. (2015). Tumor necrosis factor-alpha confers cardioprotection through ectopic expression of keratins K8 and K18. Nat. Med. 21, 1076-1084. doi: 10.1038/nm.3925
26. Park, H., Ku, S. H., Park, H., Hong, J., Kim, D., Choi, B. R., et al. (2015). RAGE siRNA-mediated gene silencing provides cardioprotection against ventricular arrhythmias in acute ischemia and reperfusion. J. Control. Release 217, 315-326. doi: 10.1016/j.jconrel.2015.09.006
27. Penna, C., Perrelli, M. G., and Pagliaro, P. (2013). Mitochondrial pathways, permeability transition pore, and redox signaling in cardioprotection: therapeutic implications. Antioxid. Redox Signal. 18, 556-599. doi: 10.1111/bph.12975
28. Phillips, J. W., Barringhaus, K. G., Sanders, J. M., Yang, Z., Chen, M., Hesselbacher, S., et al. (2003). Rosiglitazone reduces the accelerated neointima formation after arterial injury in a mouse injury model of type 2 diabetes. Circulation 108, 1994-1999. doi: 10.1161/01.CIR.0000092886.52404.50
29. Sag, C. M., Wagner, S., and Maier, L. S. (2013). Role of oxidants on calcium and sodium movement in healthy and diseased cardiac myocytes. Free Radic. Biol. Med. 63, 338-349. doi: 10.1016/j.freeradbiomed.2013.05.035
30. Steven, S., Oelze, M., Hanf, A., Kröller-Schön, S., Kashani, F., Roohani, S., et al. (2017). The SGLT2 inhibitor empagliflozin improves the primary diabetic complications in ZDF rats. Redox Biol. 13, 370-385. doi: 10.1016/j.redox.2017.06.009
31. Su, S. A., Yang, D., Zhu, W., Cai, Z., Zhang, N., Zhao, L., et al. (2016). Interleukin-17A mediates cardiomyocyte apoptosis through Stat3-iNOS pathway. Biochim. Biophys. Acta 1863, 2784-2794. doi: 10.1016/j.bbamcr.2016.08.013
32. Surwit, R. S., Kuhn, C. M., Cochrane, C., McCubbin, J. A., and Feinglos, M. N. (1988). Diet-induced type II diabetes in C57BL/6J mice. Diabetes 37, 1163-1167. doi: 10.2337/diab.37.9.1163
33. Togliatto, G., Trombetta, A., Dentelli, P., Rosso, A., and Brizzi, M. F. (2011). MIR221/MIR222-driven post-transcriptional regulation of P27KIP1 and P57KIP2 is crucial for high-glucose-and AGE-mediated vascular cell damage. Diabetologia 54, 1930-1940. doi: 10.1007/s00125-011-2125-5
34. Vettor, R., Inzucchi, S. E., and Fioretto, P. (2017). The cardiovascular benefits of empagliflozin: SGLT2-dependent and-independent effects. Diabetologia 60, 395-398. doi: 10.1007/s00125-016-4194-y
35. Wenzel, P., Hink, U., Oelze, M., Schuppan, S., Schaeuble, K., Schildknecht, S., et al. (2007). Role of reduced lipoic acid in the redox regulation of mitochondrial aldehyde dehydrogenase (ALDH-2) activity. Implications for mitochondrial oxidative stress and nitrate tolerance. J Biol Chem. 282, 792-799. doi: 10.1074/jbc.M606477200
36. Yanagisawa, K., Makita, Z., Shiroshita, K., Ueda, T., Fusegawa, T., Kuwajima, S., et al. (1998). Specific fluorescence assay for advanced glycation end products in blood and urine of diabetic patients. Metab. Clin. Exp. 47, 1348-1353. doi: 10.1016/S0026-0495(98)90303-1
37. Yu, Z., Zhang, W., and Kone, B. C. (2002). Signal transducers and activators of transcription 3 (STAT3) inhibits transcription of the inducible nitric oxide synthase gene by interacting with nuclear factor kappaB. Biochem. J. 367, 97-105. doi: 10.1042/bj20020588