Podłoże molekularne niewydolności serca w cukrzycy – nowe możliwości terapeutyczne
Magdalena Łukawska-Tatarczuk 1 , Beata Mrozikiewicz-Rakowska 2 , Edward Franek 1 , Leszek Czupryniak 2Abstrakt
Jak dowiedziono, choroby układu sercowo-naczyniowego występują kilkakrotnie częściej u chorych z cukrzycą niż w populacji ogólnej. Dlaczego tak się dzieje, mimo wielu przeprowadzonych badań i postawionych hipotez, nadal nie wyjaśniono. Uwzględniając częste współwystępowanie czynników ryzyka sercowo-naczyniowego z cukrzycą, wyodrębnianie kardiomiopatii cukrzycowej jako jej niezależnego powikłania budzi kontrowersje, a rozpoznanie w praktyce klinicznej pozostaje rzadkie. Niemniej jednak obecność cukrzycy znacznie pogarsza przebieg i rokowanie chorób układu krążenia, a lepsze poznanie komponenty cukrzycowej w rozwoju niewydolności serca wydaje się podstawowym w poszukiwaniu skutecznej terapii. Za czynniki patogenetyczne rozwoju niewydolności serca w cukrzycy uważa się: zaburzenia metaboliczne związane z hiperglikemią, lipotoksyczność, insulinooporność, stres oksydacyjny, dysfunkcję układu immunologicznego, predyspozycje genetyczne oraz zaburzenia epigenetyczne. Obraz kliniczny kardiomiopatii cukrzycowej różni się w zależności od typu cukrzycy, a dysfunkcja obejmuje nie tylko komórki miokardium, ale również komórki podścieliska, śródbłonka i układu nerwowego. Długotrwały i bezobjawowy przebieg tego powikłania oraz jego postępujący charakter skrócający życie chorych na cukrzycę skłaniają do poszukiwania nowych metod diagnostycznych i terapeutycznych. W poszukiwaniach niezbędne wydaje się lepsze poznanie podłoża molekularnego dysfunkcji mięśnia sercowego w cukrzycy. Zatrzymanie „kaskady” szlaków odpowiadających za aktywację stanu zapalnego, włóknienie czy apoptozę w poszczególnych narządach mogłoby skutecznie zapobiec rozwojowi powikłań cukrzycowych. W artykule przedstawiono dotychczasowe koncepcje patogenetyczne oraz wynikające z nich implikacje terapeutyczne, które być może będą wykorzystane w prewencji powikłań sercowo-naczyniowych w cukrzycy oraz umożliwią indywidualizację terapii.
Przypisy
- 1. Abd-El Aziz F.M., Abdelghaffar S., Hussien E.M., Fattouh A.M.:Evaluation of cardiac functions in children and adolescents withtype 1 diabetes. J. Cardiovasc. Ultrasound., 2017; 25: 12–19 2 Abdelsamia E.M., Khaleel S.A., Balah A., Abdel Baky N.A.: Curcuminaugments the cardioprotective effect of metformin in anexperimental model of type I diabetes mellitus; Impact of Nrf2/HO-1 and JAK/STAT pathways. Biomed. Pharmacother., 2019; 109:2136–2144
Google Scholar - 2. (AT2) receptors prevents myocardial hypertrophy in Zucker diabeticfatty rats. Acta Diabetol., 2019; 56: 97–104
Google Scholar - 3. Al-Malki W.H., Abdel-Raheem I.T., Dawoud M.Z., Abdou R.F.:6-shogaol protects against diabetic nephropathy and cardiomyopathyvia modulation of oxidative stress/NF-κB pathway. Pak.J. Pharm. Sci., 2018; 31: 2109–2117
Google Scholar - 4. Andersson C., Olesen J.B., Hansen P.R., Weeke P., Norgaard M.L.,Jørgensen C.H., Lange T., Abildstrøm S.Z., Schramm T.K., Vaag A.,Køber L., Torp-Pedersen C., Gislason G.H.: Metformin treatmentis associated with a low risk of mortality in diabetic patients withheart failure: A retrospective nationwide cohort study. Diabetologia,2010; 53: 2546–2553
Google Scholar - 5. Bagul P.K., Dinda A.K., Banerjee S.K.: Effect of resveratrol on sirtuinsexpression and cardiac complications in diabetes. Biochem.Biophys. Res. Commun., 2015; 468: 221–227
Google Scholar - 6. Barbati S.A., Colussi C., Bacci L., Aiello A., Re A., Stigliano E.,Isidori A.M., Grassi C., Pontecorvi A., Farsetti A., Gaetano C., NanniS.: Transcription factor CREM mediates high glucose response incardiomyocytes and in a male mouse model of prolonged hyperglycemia.Endocrinology, 2017: 158: 2391–2405
Google Scholar - 7. Behram Kandemir Y., Guntekin U., Tosun V., Korucuk N., BozdemirM.N.: Melatonin protects against streptozotocin-induceddiabetic cardiomyopathy by the phosphorylation of vascular endothelialgrowth factor-A (VEGF-A). Cell. Mol. Biol., 2018; 64: 47–52
Google Scholar - 8. Brownlee M.: Glycation products and the pathogenesis of diabeticcomplications. Diabetes Care, 1992; 15:1835–1843
Google Scholar - 9. Brownlee M.: Biochemistry and molecular cell biology of diabeticcomplications. Nature, 2001; 414: 813–820
Google Scholar - 10. Brownlee M.: The pathobiology of diabetic complications:A unifying mechanism. Diabetes, 2006; 54: 615–625
Google Scholar - 11. Brunvand L., Heier M., Brunborg C., Hanssen K.F., FugelsethD., Stensaeth K.H., Dahl-Jørgensen K., Margeirsdottir H.D.: Advancedglycation end products in children with type 1 diabetesand early reduced diastolic heart function. BMC Cardiovasc. Disord.,2017; 17: 133
Google Scholar - 12. Castoldi G., di Gioia C.R.T., Roma F., Carletti R., Manzoni G.,Stella A., Zerbini G., Perseghin G.: Activation of angiotensin type
Google Scholar - 13. Cecchi E., Pomari F., Brusasco G., Angelino P., Blatto A., GambaS., Demarie D., Moratti M., Ghisio A., Gaschino G. i wsp.: Preclinicalleft ventricular diastolic dysfunction in insulin-dependent diabetes.G. Ital. Cardiol., 1994; 24: 839–844
Google Scholar - 14. Ceriello A.: Hypothesis: The “metabolic memory”, the newchallenge of diabetes. Diabetes Res. Clin. Pract., 2009; 86: S2–S6
Google Scholar - 15. Ceriello A., Ihnat M.A., Thorpe J.E.: The “metabolic memory”:Is more than just tight glucose control necessary to prevent diabeticcomplications? J. Clin. Endocrinol. Metab., 2009; 94: 410–415
Google Scholar - 16. Chengji W., Xianjin F.: Treadmill exercise alleviates diabeticcardiomyopathy by suppressing plasminogen activator inhibitorexpression and enhancing eNOS in streptozotocin-induced malediabetic rats. Endocr. Connect., 2018; 7: 553–559
Google Scholar - 17. Clark R.J., McDonough P.M., Swanson E., Trost S.U., SuzukiM., Fukuda M., Dillmann W.H.: Diabetes and the accompanyinghyperglycemia impairs cardiomyocyte calcium cycling throughincreased nuclear O-GlcNAcylation. J. Biol. Chem., 2003; 278: 44230–44237
Google Scholar - 18. El-Osta A., Brasacchio D., Yao D., Pocai A., Jones P.L., RoederR.G., Cooper M.E., Brownlee M.: Transient high glucose causespersistent epigenetic changes and altered gene expression duringsubsequent normoglycemia. J. Exp. Med., 2008; 205: 2409–2417
Google Scholar - 19. Gaede P., Vedel P., Larsen N., Jensen G.V., Parving H.H., PedersenO.: Multifactorial intervention and cardiovascular disease inpatients with type 2 diabetes. N. Engl. J. Med., 2003; 348: 383–393
Google Scholar - 20. Gagnum V., Stene L.C., Jenssen T.G., Berteussen L.M., SandvikL., Joner G., Njølstad P.R., Skrivarhaug T.: Causes of death inchildhood-onset Type 1 diabetes: Long-term follow-up. Diabet.Med., 2017; 34: 56–63
Google Scholar - 21. Ghosh N., Katare R.: Molecular mechanism of diabetic cardiomyopathyand modulation of microRNA function by syntheticoligonucleotides. Cardiovasc. Diabetol., 2018; 17: 43
Google Scholar - 22. Guo R., Nair S.: Role of microRNA in diabetic cardiomyopathy:From mechanism to intervention. Biochim. Biophys. Acta Mol. Basis.Dis., 2017; 1863: 2070–2077
Google Scholar - 23. Guo S., Meng X.W., Yang X.S., Liu X.F., Ou-Yang C.H., Liu C.:Curcumin administration suppresses collagen synthesis in thehearts of rats with experimental diabetes. Acta Pharmacol. Sin.,2018; 39: 195–204
Google Scholar - 24. Guo X., Xue M., Li C.J., Yang W., Wang S.S., Ma Z.J., Zhang X.N.,Wang XY, Zhao R., Chang B.C., Chen L.M.: Protective effects of triptolideon TLR4 mediated autoimmune and inflammatory responseinduced myocardial fibrosis in diabetic cardiomyopathy. J. Ethnopharmacol.,2016; 193: 333–344
Google Scholar - 25. Hanefeld M., Fischer S., Julius U., Schulze J., Schwanebeck U.,Schmechel H., Ziegelasch H.J., Lindner J., The DIS Group: Risk factorsfor myocardial infarction and death in newly detected NIDDM:The Diabetes Intervention Study, 11-year follow-up. Diabetologia,1996; 39: 1577–1583
Google Scholar - 26. Hodzic A., Ribault V., Maragnes P., Milliez P., Saloux E., LabombardaF.: Decreased regional left ventricular myocardial strain intype 1 diabetic children: A first sign of diabetic cardiomyopathy?J. Transl. Int. Med., 2016; 4: 81–87
Google Scholar - 27. Hoffman W.H., Passmore G.G., Hannon D.W., Talor M.V., FoxP., Brailer C., Haislip D., Keel C., Harris G., Rose N.R., Fiordalisi I.,Čiháková D.: Increased systemic Th17 cytokines are associated withdiastolic dysfunction in children and adolescents with diabeticketoacidosis. PLoS One, 2013; 8: e71905
Google Scholar - 28. Hoffman W., Sharma M., Cihakova D., Talor M.V., Rose N.R.,Mohanakumar T., Passmore G.G.: Cardiac antibody production toself-antigens in children and adolescents during and following thecorrection of severe diabetic ketoacidosis. Autoimmunity, 2016;49: 188–196
Google Scholar - 29. Jia G., Habibi J., Bostick B.P., Ma L., DeMarco V.G., Aroor A.R.,Hayden M.R., Whaley-Connell A.T., Sowers J.R.: Uric acid promotesleft ventricular diastolic dysfunction in mice fed a Western diet.Hypertension, 2015; 65: 531–539
Google Scholar - 30. Kanamori H., Takemura G., Goto K., Tsujimoto A., Mikami A.,Ogino A., Watanabe T., Morishita K., Okada H., Kawasaki M., SeishimaM., Minatoguchi S.: Autophagic adaptations in diabetic cardiomyopathydiffer between type 1 and type 2 diabetes. Autophagy,2015; 11: 1146–1160
Google Scholar - 31. Kandemir Y.B., Tosun V., Güntekin U.: Melatonin protectsagainst streptozotocin-induced diabetic cardiomyopathy throughthe mammalian target of rapamycin (mTOR) signaling pathway.Adv. Clin. Exp. Med., 2019; 28: 1171–1177
Google Scholar - 32. Kannel W.B., Hjortland M., Castelli W.P.: Role of diabetes incongestive heart failure: The Framingham study. Am. J. Cardiol.,1974; 34: 29–34
Google Scholar - 33. Karbasforooshan H., Karimi G.: The role of SIRT1 in diabeticcardiomyopathy. Biomed. Pharmacother., 2017; 90: 386–392
Google Scholar - 34. Kim J.A., Jang H.J., Martinez-Lemus L.A., Sowers J.R.: Activationof mTOR/p70S6 kinase by ANG II inhibits insulin-stimulatedendothelial nitric oxide synthase and vasodilation. Am. J. Physiol.Endocrinol. Metab., 2012; 302: E201–E208
Google Scholar - 35. Kolm-Litty V., Sauer U., Nerlich A., Lehmann R., Schleicher E.D.:High glucose-induced transforming growth factor beta1 productionis mediated by the hexosamine pathway in porcine glomerularmesangial cells. J. Clin. Invest., 1998; 101: 160–169
Google Scholar - 36. Lee T.W., Bai K.J., Lee T.I., Chao T.F., Kao Y.H., Chen Y.J.: PPARsmodulate cardiac metabolism and mitochondrial function in diabetes.J. Biomed. Sci., 2017; 24: 5
Google Scholar - 37. Leyden D. Asthma und diabetes mellitus. Zeitschr. Klin. Med.,1881; 3: 358–364
Google Scholar - 38. Li C., Zhang J., Xue M., Li X., Han F., Liu X., Xu L., Lu Y., ChengY., Li T., Yu X., Sun B., Chen L.: SGLT2 inhibition with empagliflozinattenuates myocardial oxidative stress and fibrosis in diabeticmice heart. Cardiovasc. Diabetol., 2019; 18: 15
Google Scholar - 39. Li N., Wu H., Geng R., Tang Q.: Identification of core gene biomarkersin patients with diabetic cardiomyopathy. Dis. Markers,2018; 2018: 6025061
Google Scholar - 40. Lind M., Bounias I., Olsson M., Gudbjörnsdottir S., SvenssonA.M., Rosengren A.: Glycaemic control and incidence of heart failurein 20,985 patients with type 1 diabetes: An observational study.Lancet, 2011; 378: 140–146
Google Scholar - 41. Lundbaek K.: Is there a diabetic cardiopathy? W: Pathogenetischefaktoren des myokardinfarkts. red.: G. Schettler, Stuttgart1969: 63–71
Google Scholar - 42. Malek V., Gaikwad A.B.: Telmisartan and thiorphan combinationtreatment attenuates fibrosis and apoptosis in preventingdiabetic cardiomyopathy. Cardiovasc. Res., 2019; 115: 373–384
Google Scholar - 43. Marso S.P., Bain S.C., Consoli A., Eliaschewitz F.G., Jódar E.,Leiter L.A., Lingvay I., Rosenstock J., Seufert J., Warren M.L., WooV., Hansen O., Holst A.G., Pettersson J., Vilsbøll T. i wsp.: Semaglutideand cardiovascular outcomes in patients with type 2 diabetes.N. Engl. J. Med., 2016; 375: 1834–1844
Google Scholar - 44. Marso S.P., Daniels G.H., Brown-Frandsen K., Kristensen P.,Mann J.E., Nauck M.A., Nissen S.E., Pocock S., Poulter N.R., RavnL.S., Steinberg W.M., Stocker M., Zinman B., Bergenstal R.M., BuseJ.B. i wsp.: Liraglutide and cardiovascular outcomes in type 2 diabetes.N. Engl. J. Med., 2016; 375: 311–322
Google Scholar - 45. Mrozikiewicz-Rakowska B., Łukawska M., Nehring P.,Szymański K., Sobczyk-Kopcioł A., Krzyżewska M., Maroszek P.,Płoski R., Czupryniak L.: Genetic predictors associated with diabeticretinopathy in patients with diabetic foot. Pol. Arch. Intern.Med., 2018; 128: 35–42
Google Scholar - 46. Mrozikiewicz-Rakowska B., Maroszek P., Nehring P., Sobczyk-Kopciol A., Krzyzewska M., Kaszuba A.M., Łukawska M., ChojnowskaN., Kozka M., Bujalska-Zadrozny M., Ploski R., Krzymien J.,Czupryniak L.: Genetic and environmental predictors of chronickidney disease in patients with type 2 diabetes and diabetic footulcer: A pilot study. J. Physiol. Pharmacol., 2015; 66: 751–761
Google Scholar - 47. Mrozikiewicz-Rakowska B., Nehring P., Szymański K., Sobczyk-Kopcioł A., Płoski R., Drygas W., Krzymień J., Acharya N.A., Czupryniak L., Przybyłkowski A.: Selected RANKL/RANK/OPG systemgenetic variants in diabetic foot patients. J. Diabetes. Metab.Disord., 2018; 17: 287–296
Google Scholar - 48. Neal B., Perkovic V., Mahaffey K.W., de Zeeuw D., Fulcher G.,Erondu N., Shaw W., Law G., Desai M., Matthews D.R., CANVAS ProgramCollaborative Group: Canagliflozin and cardiovascular andrenal events in type 2 diabetes. N. Engl. J. Med., 2017; 377: 644–657
Google Scholar - 49. Nemoto O., Kawaguchi M., Yaoita H. Miyake K., Maehara K.,Maruyama Y.: Left ventricular dysfunction and remodeling instreptozotocin-induced diabetic rats. Circ. J., 2006; 70: 327–334
Google Scholar - 50. Nichols G.A., Gullion C.M., Koro C.E., Ephross S.A, Brown J.B.:The incidence of congestive heart failure in type 2 diabetes: Anupdate. Diabetes Care, 2004; 27: 1879–1884
Google Scholar - 51. Nicolino A., Longobardi G., Furgi G., Rossi M., Zoccolillo N.,Ferrara N., Rengo F.: Left ventricular diastolic filling in diabetesmellitus with and without hypertension. Am. J. Hypertens., 1995;8: 382–389
Google Scholar - 52. Ohkuma T., Komorita Y., Peters S.A.E., Woodward M.: Diabetesas a risk factor for heart failure in women and men: A systematicreview and meta-analysis of 47 cohorts including 12 million individuals.Diabetologia, 2019; 62: 1550–1560
Google Scholar - 53. Patel A., MacMahon S., Chalmers J., Neal B., Billot L., WoodwardM., Marre M., Cooper M., Glasziou P., Grobbee D., Hamet P., HarrapS., Heller S., Liu L., Mancia G. i wsp.: Intensive blood glucosecontrol and vascular outcomes in patients with type 2 diabetes.N. Engl. J. Med., 2008; 358: 2560–2572
Google Scholar - 54. Poirier P., Bogaty P., Garneau C., Marois L., Dumesnil J.G.: Diastolicdysfunction in normotensive men with well-controlledtype 2 diabetes: Importance of maneuvers in echocardiographicscreening for preclinical diabetic cardiomyopathy. Diabetes Care,2001; 24: 5–10
Google Scholar - 55. Riddle M.C.: Effects of intensive glucose lowering in the managementof patients with type 2 diabetes mellitus in the action tocontrol cardiovascular risk in diabetes (ACCORD) trial. Circulation,2010; 122: 844–846
Google Scholar - 56. Rubler S., Dlugash J., Yuceoglu Y.Z., Kumral T., Branwood A.W.,Grishman A.: New type of cardiomyopathy associated with diabeticglomerulosclerosis. Am. J. Cardiol., 1972; 30: 595–602
Google Scholar - 57. Rydén L., Grant P.J., Anker S.D., Berne C., Cosentino F., DanchinN., Deaton C., Escaned J., Hammes H.P., Huikuri H., Marre M., MarxN., Mellbin L., Ostergren J., Patrono C. i wsp.: ESC Guidelines ondiabetes, pre-diabetes, and cardiovascular diseases developed incollaboration with the EASD: The Task Force on diabetes, prediabetes,and cardiovascular diseases of the European Society ofCardiology (ESC) and developed in collaboration with the EuropeanAssociation for the Study of Diabetes (EASD). Eur. Heart J.,2013; 34: 3035–3087
Google Scholar - 58. Schalkwijk C.G., Stehouwer C.D.: Vascular complications indiabetes mellitus: The role of endothelial dysfunction. Clin. Sci.,2005; 109: 143–159
Google Scholar - 59. Seferović P.M., Paulus W.J.: Clinical diabetic cardiomyopathy:A two-faced disease with restrictive and dilated phenotypes. Eur.Heart J., 2015; 36: 1718–1727
Google Scholar - 60. Siebel A.L., Fernandez A.Z., El-Osta A.: Glycemic memory associatedepigenetic changes. Biochem. Pharmacol., 2010; 80: 1853–1859
Google Scholar - 61. Song Y.L., Ford J.W., Gordon D., Shanley C.J.: Regulation of lysyloxidase by interferon-γ in rat aortic smooth muscle cells. Arterioscler.Thromb. Vasc. Biol., 2000; 20: 982–988
Google Scholar - 62. Stehouwer C.D., Lambert J., Donker A.J., van Hinsbergh V.W.:Endothelial dysfunction and pathogenesis of diabetic angiopathy.Cardiovasc. Res., 1997; 34: 55–68
Google Scholar - 63. Stratton I.M., Adler A.I., Neil H.A., Matthews D.R., ManleyS.E., Cull C.A., Hadden D., Turner R.C., Holman R.R.: Association ofglycaemia with macrovascular and microvascular complicationsof type 2 diabetes (UKPDS 35): Prospective observational study.BMJ, 2000; 321: 405–412
Google Scholar - 64. Subramanian S., Hirsch I.B.: Intensive diabetes treatment andcardiovascular outcomes in type 1 diabetes mellitus: Implicationsof the diabetes control and complications trial/epidemiology ofdiabetes interventions and complications study 30-year follow-up.Endocrinol. Metab. Clin. North Am., 2018; 47: 65–79
Google Scholar - 65. Sundgren N.C., Giraud G.D., Schultz J.M., Lasarev M.R., StorkP.J., Thornburg K.L.: Extracellular signal-regulated kinase andphosphoinositol-3 kinase mediate IGF-1 induced proliferation offetal sheep cardiomyocytes. Am. J. Physiol. Regul. Integr. Comp.Physiol., 2003; 285: R1481–R1489
Google Scholar - 66. Vaur L., Gueret P., Lievre M., Chabaud S., Passa P., DIABHYCARStudy Group (type 2 DIABetes, Hypertension, CARdiovascularEvents and Ramipril) study: Development of congestive heartfailure in type 2 diabetic patients with microalbuminuria or proteinuria:Observations from the DIABHYCAR (type 2 DIABetes, Hypertension,CArdiovascular Events and Ramipril) study. DiabetesCare, 2003; 26: 855–860
Google Scholar - 67. Vinik A.I.: Diabetic neuropathy: Pathogenesis and therapy.Am. J. Med.,1999; 107: 17S–26S
Google Scholar - 68. Wai B., Patel S.K., Ord M., MacIsaac R.J, Jerums G., SrivastavaP.M., Burrell L.M.: Prevalence, predictors and evolution of echocardiographicallydefined cardiac abnormalities in adults with type 1 diabetes: An observational cohort study. J. Diabetes Complications,2014; 28: 22–28
Google Scholar - 69. Waldman M., Cohen K., Yadin D., Nudelman V., Gorfil D., Laniado-Schwartzman M., Kornwoski R., Aravot D., Abraham N.G.,Arad M., Hochhauser E.: Regulation of diabetic cardiomyopathy bycaloric restriction is mediated by intracellular signaling pathwaysinvolving ‘SIRT1 and PGC-1α’. Cardiovasc. Diabetol., 2018; 17: 111
Google Scholar - 70. Wu L., Wang K., Wang W., Wen Z., Wang P., Liu L., Wang D.W.:Glucagon-like peptide-1 ameliorates cardiac lipotoxicity in diabeticcardiomyopathy via the PPARα pathway. Aging Cell., 2018;17: e12763
Google Scholar - 71. Xu W., Chen J., Lin J., Liu D., Mo L., Pan W., Feng J., Wu W., ZhengD.: Exogenous H2S protects H9c2 cardiac cells against high glucoseinducedinjury and inflammation by inhibiting the activation ofthe NF-κB and IL-1β pathways. Int. J. Mol. Med., 2015; 35: 177–186
Google Scholar - 72. Yancy C.W., Jessup M., Bozkurt B., Butler J., Casey D.E. Jr.,Drazner M.H., Fonarow G.C., Geraci S.A., Horwich T., Januzzi J.L.,Johnson M.R., Kasper E.K., Levy W.C., Masoudi F.A., McBride P.E.i wsp.: 2013 ACCF/AHA guideline for the management of heartfailure: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J.Am. Coll. Cardiol., 2013; 62: e147–e239
Google Scholar - 73. Yoldas T., Örün U.A., Sagsak E., Aycan Z., Kaya Ö., Özgür S.,Karademir S.: Subclinical left ventricular systolic and diastolicdysfunction in type 1 diabetic children and adolescents with goodmetabolic control. Echocardiography, 2018; 35: 227–233
Google Scholar - 74. Yu Q., Vazquez R., Khojeini E.V., Patel C., Venkataramani R.,Larson D.F.: IL-18 induction of osteopontin mediates cardiac fibrosisand diastolic dysfunction in mice. Am. J. Physiol. Heart Circ.Physiol., 2009; 297: H76–H85
Google Scholar - 75. Yu Q., Vazquez R., Zabadi S., Watson R.R., Larson D.F.: T-lymphocytesmediate left ventricular fibrillar collagen cross-linkingand diastolic dysfunction in mice. Matrix Biol., 2010; 29: 511–518
Google Scholar - 76. Yu Y., Zheng G.: Troxerutin protects against diabetic cardiomyopathythrough NFκB/AKT/IRS1 in a rat model of type 2 diabetes.Mol. Med. Rep., 2017; 15: 3473–3478
Google Scholar - 77. Zhao C., Zhang Y., Liu H., Li P., Zhang H., Cheng G.: Fortunellinprotects against high fructose-induced diabetic heart injury inmice by suppressing inflammation and oxidative stress via AMPK/Nrf-2 pathway regulation. Biochem. Biophys. Res. Commun., 2017;490: 552–559
Google Scholar - 78. Zinman B., Wanner C., Lachin J.M., Fitchett D., Bluhmki E., HantelS., Mattheus M., Devins T., Johansen O.E., Woerle H.J., BroedlU.C., Inzucchi S.E: Empagliflozin, cardiovascular outcomes, andmortality in type 2 diabetes. N. Engl. J. Med., 2015; 373: 2117–2128
Google Scholar