Empagliflozin normalizes the size and number of mitochondria and prevents reduction in mitochondrial size after myocardial infarction in diabetic hearts

Physiological Reports

Volumn 6, Issue 12, 2018, Pages

  Mizuno, Masashi ^a   Kuno, Atsushi ^a   Yano, Toshiyuki ^a   Miki, Takayuki ^a   Oshima, Hiroto ^a   Sato, Tatsuya ^a   Nakata, Kei ^a   Kimura, Yukishige ^a   Tanno, Masaya ^a   Miura, Tetsuji ^a  

^a SAPPORO MEDICAL UNIVERSITY SCHOOL OF MEDICINE   (Japan)

Author keywords

Acute myocardial infarction; diabetes mellitus; empagliflozin; mitochondria; SGLT2 inhibitor

Indexed keywords

EMPAGLIFLOZIN; FAT DROPLET; MITOCHONDRIAL PROTEIN; MITOFUSIN 1; PROTEIN BNIP3; REACTIVE OXYGEN METABOLITE; SODIUM GLUCOSE COTRANSPORTER 2; TRIACYLGLYCEROL; VINCULIN; BENZHYDRYL DERIVATIVE; CHOLESTEROL; GLUCOSIDE; TTC11 PROTEIN, RAT;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; ASSISTED VENTILATION; AUTOPHAGY; BLOOD PRESSURE; CARDIAC MUSCLE CELL; CELL ULTRASTRUCTURE; CONTROLLED STUDY; CORONARY ARTERY LIGATION; DIABETIC CARDIOMYOPATHY; ELECTRON MICROSCOPY; GENE EXPRESSION; GLUCOSE BLOOD LEVEL; HEART FAILURE; HEART INFARCTION; HEART RATE; IMMUNOBLOTTING; INSULIN RESISTANCE; LIPOLYSIS; LONG EVANS TOKUSHIMA OTSUKA RAT; MALE; MITOCHONDRIAL VOLUME; MITOPHAGY; MORTALITY; MRNA EXPRESSION LEVEL; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OTSUKA LONG EVANS TOKUSHIMA FATTY RAT; POLYMERASE CHAIN REACTION; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; RAT; TISSUE LEVEL; TRANSCRIPTION REGULATION; UPREGULATION; ANIMAL; BLOOD; CELL VACUOLE; DRUG EFFECT; EXPERIMENTAL DIABETES MELLITUS; HEART MITOCHONDRION; METABOLISM; PATHOLOGY; PHARMACOLOGY; ULTRASTRUCTURE;

ANIMALS; AUTOPHAGY; BENZHYDRYL COMPOUNDS; BLOOD GLUCOSE; CHOLESTEROL; DIABETES MELLITUS, EXPERIMENTAL; DIABETES MELLITUS, TYPE 2; GLUCOSIDES; MALE; MICROSCOPY, ELECTRON; MITOCHONDRIA, HEART; MITOCHONDRIAL PROTEINS; MITOCHONDRIAL SIZE; MYOCARDIAL INFARCTION; MYOCYTES, CARDIAC; RATS, INBRED OLETF; REACTIVE OXYGEN SPECIES; SODIUM-GLUCOSE TRANSPORTER 2 INHIBITORS; TRIGLYCERIDES; VACUOLES;

EID: 85049031129     PISSN: None     EISSN: 2051817X     Source Type: Journal    
DOI: 10.14814/phy2.13741     Document Type: Article

References (62)

1. 2+ and cell death during ischaemia-reperfusion injury in cardiomyocytes. J. Physiol. 587:1331–1341.
2. Bertero, E., L. Prates Roma, P. Ameri, and C. Maack. 2017. Cardiac effects of SGLT2 inhibitors: the sodium hypothesis. Cardiovasc. Res. 114:12–18.
3. Boudina, S., S. Sena, H. Theobald, X. Sheng, J. J. Wright, X. X. Hu, et al. 2007. Mitochondrial energetics in the heart in obesity-related diabetes: direct evidence for increased uncoupled respiration and activation of uncoupling proteins. Diabetes 56:2457–2466.
4. Bugger, H., and E. D. Abel. 2010. Mitochondria in the diabetic heart. Cardiovasc. Res. 88:229–240.
5. Bugger, H., S. Boudina, X. X. Hu, J. Tuinei, V. G. Zaha, H. A. Theobald, et al. 2008. Type 1 diabetic akita mouse hearts are insulin sensitive but manifest structurally abnormal mitochondria that remain coupled despite increased uncoupling protein 3. Diabetes 57:2924–2932.
6. Cherney, D. Z., B. A. Perkins, N. Soleymanlou, R. Har, N. Fagan, O. E. Johansen, et al. 2014. The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovasc. Diabetol. 13:28.
7. Dabkowski, E. R., C. L. Williamson, V. C. Bukowski, R. S. Chapman, S. S. Leonard, C. J. Peer, et al. 2009. Diabetic cardiomyopathy-associated dysfunction in spatially distinct mitochondrial subpopulations. Am. J. Physiol. Heart Circ. Physiol. 296:H359–H369.
8. De Luca, G., M. T. Dirksen, C. Spaulding, H. Kelbaek, M. Schalij, L. Thuesen, et al. 2013. Impact of diabetes on long-term outcome after primary angioplasty: insights from the DESERT cooperation. Diabetes Care 36:1020–1025.
9. Dorn, G. II. 2016. Mitochondrial fission/fusion and cardiomyopathy. Curr. Opin. Genet. Dev. 38:38–44.
10. Ferrannini, E., E. Muscelli, S. Frascerra, S. Baldi, A. Mari, T. Heise, et al. 2014. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J. Clin. Invest. 124:499–508.
11. Galan, D. T., V. Bito, P. Claus, P. Holemans, J. Abi-Char, C. K. Nagaraju, et al. 2016. Reduced mitochondrial respiration in the ischemic as well as in the remote nonischemic region in postmyocardial infarction remodeling. Am. J. Physiol. Heart Circ. Physiol. 311:H1075–H1090.
12. Galloway, C. A., and Y. Yoon. 2012. Perspectives on: SGP symposium on mitochondrial physiology and medicine: what comes first, misshape or dysfunction? The view from metabolic excess. J. Gen. Physiol. 139:455–463.
13. Guglielmino, K., K. Jackson, T. R. Harris, V. Vu, H. Dong, G. Dutrow, et al. 2012. Pharmacological inhibition of soluble epoxide hydrolase provides cardioprotection in hyperglycemic rats. Am. J. Physiol. Heart Circ. Physiol. 303:H853–H862.
14. Habibi, J., A. R. Aroor, J. R. Sowers, G. Jia, M. R. Hayden, M. Garro, 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.
15. Hammoudi, N., D. Jeong, R. Singh, A. Farhat, M. Komajda, E. Mayoux, et al. 2017. Empagliflozin improves left ventricular diastolic dysfunction in a genetic model of type 2 diabetes. Cardiovasc. Drugs Ther. 31:233–246.
16. Hayashi, T., T. Mori, K. Sohmiya, Y. Okada, S. Inamoto, N. Okuda, et al. 2003. Efficacy of edaravone, a free radical scavenger, on left ventricular function and structure in diabetes mellitus. J. Cardiovasc. Pharmacol. 41:923–929.
17. Hearse, D. J., V. Richard, D. M. Yellon, and J. G. Jr Kingma. 1988. Evolving myocardial infarction in the rat in vivo: an inappropriate model for the investigation of drug-induced infarct size limitation during sustained regional ischaemia. J. Cardiovasc. Pharmacol. 11:701–710.
18. Hotta, H., T. Miura, T. Miki, N. Togashi, T. Maeda, S. J. Kim, et al. 2010. Angiotensin II type 1 receptor-mediated upregulation of calcineurin activity underlies impairment of cardioprotective signaling in diabetic hearts. Circ. Res. 106:129–132.
19. Huang, Q., L. Zhan, H. Cao, J. Li, Y. Lyu, X. Guo, et al. 2016. Increased mitochondrial fission promotes autophagy and hepatocellular carcinoma cell survival through the ROS-modulated coordinated regulation of the NFKB and TP53 pathways. Autophagy 12:999–1014.
20. Ide, T., H. Tsutsui, S. Hayashidani, D. Kang, N. Suematsu, K. Nakamura, et al. 2001. Mitochondrial DNA damage and dysfunction associated with oxidative stress in failing hearts after myocardial infarction. Circ. Res. 88:529–535.
21. Ito, D., S. Shimizu, K. Inoue, D. Saito, M. Yanagisawa, K. Inukai, et al. 2017. Comparison of ipragliflozin and pioglitazone effects on nonalcoholic fatty liver disease in patients with type 2 diabetes: a randomized, 24-week, open-label, active-controlled trial. Diabetes Care 40:1364–1372.
22. Jezek, J., K. F. Cooper, and R. Strich. 2018. Reactive oxygen species and mitochondrial dynamics: the yin and yang of mitochondrial dysfunction and cancer progression. Antioxidants (Basel) 7:E13.
23. Joubert, M., B. Jagu, D. Montaigne, X. Marechal, A. Tesse, A. Ayer, et al. 2017. The Sodium-Glucose Cotransporter 2 Inhibitor Dapagliflozin Prevents Cardiomyopathy in a Diabetic Lipodystrophic Mouse Model. Diabetes 66:1030–1040.
24. Kouzu, H., T. Miki, M. Tanno, A. Kuno, T. Yano, T. Itoh, et al. 2015. Excessive degradation of adenine nucleotides by up-regulated AMP deaminase underlies afterload-induced diastolic dysfunction in the type 2 diabetic heart. J. Mol. Cell. Cardiol. 80:136–145.
25. Kuramoto, K., T. Okamura, T. Yamaguchi, T. Y. Nakamura, S. Wakabayashi, H. Morinaga, et al. 2012. Perilipin 5, a lipid droplet-binding protein, protects heart from oxidative burden by sequestering fatty acid from excessive oxidation. J. Biol. Chem. 287:23852–23863.
26. de Leeuw, A. E., and R. A. de Boer. 2016. Sodium-glucose cotransporter 2 inhibition: cardioprotection by treating diabetes-a translational viewpoint explaining its potential salutary effects. Eur. Heart J. Cardiovasc Pharmacother. 2:244–255.
27. Liesa, M., M. Palacin, and A. Zorzano. 2009. Mitochondrial dynamics in mammalian health and disease. Physiol. Rev. 89:799–845.
28. Listenberger, L. L., X. Han, S. E. Lewis, S. Cases, R. V. Jr Farese, D. S. Ory, et al. 2003. Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc. Natl Acad. Sci. USA 100:3077–3082.
29. Loson, O. C., Z. Song, H. Chen, and D. C. Chan. 2013. Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission. Mol. Biol. Cell 24:659–667.
30. Luo, M., X. Guan, E. D. Luczak, D. Lang, W. Kutschke, Z. Gao, et al. 2013. Diabetes increases mortality after myocardial infarction by oxidizing CaMKII. J. Clin. Invest. 123:1262–1274.
31. MacDonald, J. R., M. Oellermann, S. Rynbeck, G. Chang, K. Ruggiero, G. J. Cooper, et al. 2011. Transmural differences in respiratory capacity across the rat left ventricle in health, aging, and streptozotocin-induced diabetes mellitus: evidence that mitochondrial dysfunction begins in the subepicardium. Am. J. Physiol. Cell Physiol. 300:C246–C255.
32. MacVicar, T., and T. Langer. 2016. OPA1 processing in cell death and disease - the long and short of it. J. Cell Sci. 129:2297–2306.
33. Marso, S. P., T. Miller, B. D. Rutherford, R. J. Gibbons, M. Qureshi, A. Kalynych, et al. 2007. Comparison of myocardial reperfusion in patients undergoing percutaneous coronary intervention in ST-segment elevation acute myocardial infarction with versus without diabetes mellitus (from the EMERALD Trial). Am. J. Cardiol. 100:206–210.
34. Maxwell, M. P., D. J. Hearse, and D. M. Yellon. 1987. Species variation in the coronary collateral circulation during regional myocardial ischaemia: a critical determinant of the rate of evolution and extent of myocardial infarction. Cardiovasc. Res. 21:737–746.
35. Mellor, H. R., K. M. Rouschop, S. M. Wigfield, B. G. Wouters, and A. L. Harris. 2010. Synchronised phosphorylation of BNIP3, Bcl-2 and Bcl-xL in response to microtubule-active drugs is JNK-independent and requires a mitotic kinase. Biochem. Pharmacol. 79:1562–1572.
36. Miki, T., T. Miura, H. Hotta, M. Tanno, T. Yano, T. Sato, et al. 2009. Endoplasmic reticulum stress in diabetic hearts abolishes erythropoietin-induced myocardial protection by impairment of phospho-glycogen synthase kinase-3beta-mediated suppression of mitochondrial permeability transition. Diabetes 58:2863–2872.
37. Mizushima, N., Y. Ohsumi, and T. Yoshimori. 2002. Autophagosome formation in mammalian cells. Cell Struct. Funct. 27:421–429.
38. Montaigne, D., X. Marechal, A. Coisne, N. Debry, T. Modine, G. Fayad, et al. 2014. Myocardial contractile dysfunction is associated with impaired mitochondrial function and dynamics in type 2 diabetic but not in obese patients. Circulation 130:554–564.
39. Mudaliar, S., S. Alloju, and R. R. Henry. 2016. Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME Study? a unifying hypothesis. Diabetes Care 39:1115–1122.
40. Murase, H., A. Kuno, T. Miki, M. Tanno, T. Yano, H. Kouzu, et al. 2015. Inhibition of DPP-4 reduces acute mortality after myocardial infarction with restoration of autophagic response in type 2 diabetic rats. Cardiovasc. Diabetol. 14:103.
41. Muratsubaki, S., A. Kuno, M. Tanno, T. Miki, T. Yano, H. Sugawara, et al. 2017. Suppressed autophagic response underlies augmentation of renal ischemia/reperfusion injury by type 2 diabetes. Sci. Rep. 7:5311.
42. Neal, B., V. Perkovic, K. W. Mahaffey, D. de Zeeuw, G. Fulcher, N. Erondu, et al. 2017. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N. Engl. J. Med. 377:644–657.
43. Nguyen, T. N., B. S. Padman, and M. Lazarou. 2016. Deciphering the molecular signals of PINK1/Parkin mitophagy. Trends Cell Biol. 26:733–744.
44. Oelze, M., S. Kroller-Schon, P. Welschof, T. Jansen, M. Hausding, Y. Mikhed, 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.
45. Oshima, H., M. Mizuno, T. Miki, A. Kuno, K. Nakata, Y. Kimura, et al. 2017. Empagliflozin, an SGLT2 inhibitor, improves survival after myocardial infarction in diabetic rats by up-regulating anti-oxidative stress proteins. Diabetologia 60:(Supple I), S32.
46. Picard, M., I. Azuelos, B. Jung, C. Giordano, S. Matecki, S. Hussain, et al. 2015. Mechanical ventilation triggers abnormal mitochondrial dynamics and morphology in the diaphragm. J. Appl. Physiol. (1985) 118:1161–1171.
47. Prieto, J., M. Leon, X. Ponsoda, R. Sendra, R. Bort, R. Ferrer-Lorente, et al. 2016. Early ERK1/2 activation promotes DRP1-dependent mitochondrial fission necessary for cell reprogramming. Nat. Commun. 7:11124.
48. Qi, X., M. H. Disatnik, N. Shen, R. A. Sobel, and D. Mochly-Rosen. 2011. Aberrant mitochondrial fission in neurons induced by protein kinase C{delta} under oxidative stress conditions in vivo. Mol. Biol. Cell 22:256–265.
49. Schulze, P. C., K. Drosatos, and I. J. Goldberg. 2016. Lipid Use and Misuse by the Heart. Circ. Res. 118:1736–1751.
50. Shenouda, S. M., M. E. Widlansky, K. Chen, G. Xu, M. Holbrook, C. E. Tabit, et al. 2011. Altered mitochondrial dynamics contributes to endothelial dysfunction in diabetes mellitus. Circulation 124:444–453.
51. Shirakabe, A., P. Zhai, Y. Ikeda, T. Saito, Y. Maejima, C. P. Hsu, et al. 2016. Drp1-dependent mitochondrial autophagy plays a protective role against pressure overload-induced mitochondrial dysfunction and heart failure. Circulation 133:1249–1263.
52. Singh, M. V., P. D. Swaminathan, E. D. Luczak, W. Kutschke, R. M. Weiss, and M. E. Anderson. 2012. MyD88 mediated inflammatory signaling leads to CaMKII oxidation, cardiac hypertrophy and death after myocardial infarction. J. Mol. Cell. Cardiol. 52:1135–1144.
53. Suzuki, M., M. Takeda, A. Kito, M. Fukazawa, T. Yata, M. Yamamoto, et al. 2014. Tofogliflozin, a sodium/glucose cotransporter 2 inhibitor, attenuates body weight gain and fat accumulation in diabetic and obese animal models. Nutr. Diabetes 4:e125.
54. Taguchi, N., N. Ishihara, A. Jofuku, T. Oka, and K. Mihara. 2007. Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission. J. Biol. Chem. 282:11521–11529.
55. Takada, A., T. Miki, A. Kuno, H. Kouzu, D. Sunaga, T. Itoh, et al. 2012. Role of ER stress in ventricular contractile dysfunction in type 2 diabetes. PLoS ONE 7:e39893.
56. Tanajak, P., P. Sa-Nguanmoo, S. Sivasinprasasn, S. Thummasorn, N. Siri-Angkul, S. C. Chattipakorn, et al. 2018. Cardioprotection of dapagliflozin and vildagliptin in rats with cardiac ischemia-reperfusion injury. J. Endocrinol. 236:69–84.
57. Tsushima, K., H. Bugger, A. R. Wende, J. Soto, G. A. Jenson, A. R. Tor, et al. 2017. Mitochondrial reactive oxygen species in lipotoxic hearts induce post-translational modifications of AKAP121, DRP1, and OPA1 that promote mitochondrial fission. Circ. Res. 122:58–73.
58. Xia, Y., Z. Chen, A. Chen, M. Fu, Z. Dong, K. Hu, et al. 2017. LCZ696 improves cardiac function via alleviating Drp1-mediated mitochondrial dysfunction in mice with doxorubicin-induced dilated cardiomyopathy. J. Mol. Cell. Cardiol. 108:138–148.
59. Xu, S., P. Wang, H. Zhang, G. Gong, N. Gutierrez Cortes, W. Zhu, et al. 2016. CaMKII induces permeability transition through Drp1 phosphorylation during chronic beta-AR stimulation. Nat. Commun. 7:13189.
60. Yokono, M., T. Takasu, Y. Hayashizaki, K. Mitsuoka, R. Kihara, Y. Muramatsu, et al. 2014. SGLT2 selective inhibitor ipragliflozin reduces body fat mass by increasing fatty acid oxidation in high-fat diet-induced obese rats. Eur. J. Pharmacol. 727:66–74.
61. Zhu, Y., S. Massen, M. Terenzio, V. Lang, S. Chen-Lindner, R. Eils, et al. 2013. Modulation of serines 17 and 24 in the LC3-interacting region of Bnip3 determines pro-survival mitophagy versus apoptosis. J. Biol. Chem. 288:1099-1113.
62. Zinman, B., C. Wanner, J. M. Lachin, D. Fitchett, E. Bluhmki, S. Hantel, et al. 2015. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N. Engl. J. Med. 373:2117–2128.