Skip to main content

Advertisement

SpringerLink
Log in

Metabolic Syndrome and Cardiac Remodeling Due to Mitochondrial Oxidative Stress Involving Gliflozins and Sirtuins

  • Hypertension and Obesity (E Reisin, Section Editor)
  • Published:
Current Hypertension Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

To address the mechanistic pathways focusing on mitochondria dysfunction, oxidative stress, sirtuins imbalance, and other contributors in patient with metabolic syndrome and cardiovascular disease. Sodium glucose co-transporter type 2 (SGLT-2) inhibitors deeply influence these mechanisms. Recent randomized clinical trials have shown impressive results in improving cardiac function and reducing cardiovascular and renal events. These unexpected results generate the need to deepen our understanding of the molecular mechanisms able to generate these effects to help explain such significant clinical outcomes.

Recent Findings

Cardiovascular disease is highly prevalent among individuals with metabolic syndrome and diabetes. Furthermore, mitochondrial dysfunction is a principal player in its development and persistence, including the consequent cardiac remodeling and events. Another central protagonist is the renin-angiotensin system; the high angiotensin II (Ang II) activity fuel oxidative stress and local inflammatory responses. Additionally, sirtuins decline plays a pivotal role in the process; they enhance oxidative stress by regulating adaptive responses to the cellular environment and interacting with Ang II in many circumstances, including cardiac and vascular remodeling, inflammation, and fibrosis.

Fasting and lower mitochondrial energy generation are conditions that substantially reduce most of the mentioned cardiometabolic syndrome disarrangements. In addition, it increases sirtuins levels, and adenosine monophosphate-activated protein kinase (AMPK) signaling stimulates hypoxia-inducible factor-1β (HIF-1 beta) and favors ketosis. All these effects favor autophagy and mitophagy, clean the cardiac cells with damaged organelles, and reduce oxidative stress and inflammatory response, giving cardiac tissue protection. In this sense, SGLT-2 inhibitors enhance the level of at least four sirtuins, some located in the mitochondria. Moreover, late evidence shows that SLGT-2 inhibitors mimic this protective process, improving mitochondria function, oxidative stress, and inflammation.

Summary

Considering the previously described protection at the cardiovascular level is necessary to go deeper in the knowledge of the effects of SGLT-2 inhibitors on the mitochondria function. Various of the protective effects these drugs clearly had shown in the trials, and we briefly describe it could depend on sirtuins enhance activity, oxidative stress reduction, inflammatory process attenuation, less interstitial fibrosis, and a consequent better cardiac function. This information could encourage investigating new therapeutic strategies for metabolic syndrome, diabetes, heart and renal failure, and other diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: •   Of importance •• Of major importance

  1. Virani SS, Alonso A, Aparicio HJ, Benjamin EJ, Bittencourt MS, Callaway CW, et al. Heart disease and stroke statistics—2021 update; a report from the American Heart Association. Circulation. 2021;143:e254-743.

    Article  PubMed  Google Scholar 

  2. Pan American Health Organization. WHO reveals leading causes of death and disability worldwide: 2000–2019. Available from: https://www.paho.org/en/news/9-12-2020-who-reveals-leading-causes-death-and-disability-worldwide-2000-2019.

  3. Murphy MP, Hartley RC. Mitochondria as a therapeutic target for common pathologies. Nat Rev Drug Discov. 2018;17:865–86.

    Article  CAS  PubMed  Google Scholar 

  4. Porter LC, Franczyk MP, Pietka T, Yamaguchi S, Lin JB, Sasaki Y, et al. NAD+-dependent deacetylase SIRT3 in adipocytes is dispensable for maintaining normal adipose tissue mitochondrial function and whole body metabolism. Am J Physiol Endocrinol Metab. 2018;315:E520-530.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ilkun O, Boudina S. Cardiac dysfunction and oxidative stress in the metabolic syndrome: an update on antioxidant therapies. Curr Pharm Des. 2013;19:4806–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ferder L, Inserra F, Martínez-Maldonado M. Inflammation and the metabolic syndrome: role of angiotensin II and oxidative stress. Curr Hypertens Rep. 2006;8:191–8.

    Article  CAS  PubMed  Google Scholar 

  7. Cabandugama PK, Gardner MJ, Sowers JR. The renin angiotensin aldosterone system in obesity and hypertension: roles in the cardiorenal metabolic syndrome. Med Clin North Am. 2017;101:129–37.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Verdejo HE, del Campo A, Troncoso R, Gutierrez T, Toro B, Quiroga C, et al. Mitochondria, myocardial remodeling, and cardiovascular disease. Curr Hypertens Rep. 2012;14(6):532–9.

    Article  CAS  PubMed  Google Scholar 

  9. •• de Cavanagh EM, Inserra F, Ferder L. Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition. Am J Physiol Heart Circ Physiol. 2015;309:H15–44. The authors reviewed different mechanisms and pathways mimicking calory restriction and RAS blockade in the tissues and cells' protection. They underline the down-regulation of mTOR and IGF-I and the up-regulation of klotho and sirtuins as central players. Moreover, postulate that through these mechanisms, both strategies can produce cardiovascular protection and may further extend the lifespan of mammals.

  10. Maissan P, Mooij EJ, Barberis M. Sirtuins-mediated system-level regulation of mammalian tissues at the interface between metabolism and cell cycle: a systematic review. Biology (Basel). 2021;10:194.

    CAS  PubMed  Google Scholar 

  11. Singh CK, Chhabra G, Ndiaye MA, Garcia-Peterson LM, Mack NJ, Ahmad N. The role of sirtuins in antioxidant and redox signaling. Antioxid Redox Signal. 2018;28(8):643–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Houtkooper RH, Pirinen E, Auwerx J. Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol. 2012;13(4):225–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Abadir PM, Foster DB, Crow M, Cooke CA, Rucker JJ, Jain A, et al. Identification and characterization of a functional mitochondrial angiotensin system. Proc Natl Acad Sci USA. 2011;108(36):14849–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Manucha W, Ritchie B, Ferder L. Hypertension and insulin resistance: implications of mitochondrial dysfunction. Curr Hypertens Rep. 2014;17(1):1–7.

    Google Scholar 

  15. de Cavanagh EM, Ferder M, Inserra F, Ferder L. Angiotensin II, mitochondria, cytoskeletal, and extracellular matrix connections: an integrating viewpoint. Am J Physiol Heart Circ Physiol. 2009;296:H550-558.

    Article  PubMed  Google Scholar 

  16. de Cavanagh EM, Inserra F, Ferder M, Ferder L. From mitochondria to disease: role of the renin-angiotensin system. Am J Nephrol. 2007;27:545–53.

    Article  PubMed  Google Scholar 

  17. Ricci C, Pastukh V, Schaffer SW. Involvement of the mitochondrial permeability transition pore in angiotensin II-mediated apoptosis. Exp Clin Cardiol. 2005;10(3):160–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Shokolenko IN, Wilson GL, Alexeyev MF. Aging: a mitochondrial DNA perspective, critical analysis and an update. World J Exp Med. 2014;4(4):46–57.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Merksamer PI, Liu Y, He W, Hirschey MD, Chen D, Verdin E. The sirtuins, oxidative stress and aging: an emerging link. Aging (Albany NY). 2013;5:144–50.

    Article  CAS  PubMed  Google Scholar 

  20. O’Neill S, O’Driscoll L. Metabolic syndrome: a closer look at the growing epidemic and its associated pathologies. Obes Rev. 2015;16(1):1–12.

    Article  CAS  PubMed  Google Scholar 

  21. Kalupahana NS, Moustaid-Moussa N, Claycombe KJ. Immunity as a link between obesity and insulin resistance. Mol Asp Med. 2012;33(1):26–34.

    Article  CAS  Google Scholar 

  22. Matsushima S, Sadoshima J. The role of sirtuins in cardiac disease. Am J Physiol Heart Circ Physiol. 2015;309:H1375–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Cortes-Rojo C, Vargas-Vargas MA, Olmos-Orizaba BE, Rodriguez-Orozco AR, Calderon-Cortes E. Interplay between NADH oxidation by complex I, glutathione redox state and sirtuin-3, and its role in the development of insulin resistance. Biochim Biophys Acta Mol Basis Dis. 2020;1866:165801–17.

    Article  CAS  PubMed  Google Scholar 

  24. Wu YT, Wu SB, Wei YH. Roles of sirtuins in the regulation of antioxidant defense and bioenergetic function of mitochondria under oxidative stress. Free Radic Res. 2014;48:1070–84.

    Article  CAS  PubMed  Google Scholar 

  25. Ahn BH, Kim HS, Song S, Lee IH, Liu J, Vassilopoulos A, et al. A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc Natl Acad Sci USA. 2008;105:14447–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Luo YX, Tang X, An XZ, Xie XM, Chen XF, Zhao X, et al. SIRT4 accelerates Ang II-induced pathological cardiac hypertrophy by inhibiting manganese superoxide dismutase activity. Eur Heart J. 2017;38:1389–98.

    CAS  PubMed  Google Scholar 

  27. D’Onofrio N, Servillo L, Balestrieri ML. SIRT1 and SIRT6 signaling pathways in cardiovascular disease protection. Antioxid Redox Signal. 2018;28:711–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res. 2010;107:1058–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. •• Wilson AJ, Gill EK, Abudalo RA, Edgar KS, Watson CJ, Grieve DJ. Reactive oxygen species signalling in the diabetic heart: emerging prospect for therapeutic targeting. Heart. 2018;104:293–9. This review explores the contributions of the most significant ROS sources in diabetic myocardiopathy. The authors additionally reviewed different potential strategies for targeting ROS signaling with pharmacological and non-pharmacological approaches trying to impact cardiovascular remodeling and delay the progression of myocardial damage.

    Article  CAS  PubMed  Google Scholar 

  30. Kaludercic N, Di Lisa F. Mitochondrial ROS formation in the pathogenesis of diabetic cardiomyopathy. Front Cardiovasc Med. 2020;7:12. https://doi.org/10.3389/fcvm.2020.00012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Natali A, Nesti L, Fabiani I, Calogero E, Di Bello V. Impact of empaglifozin on subclinical left ventricular dysfunctions and on the mechanisms involved in myocardial disease progression in type 2 diabetes: rationale and design of the EMPA-HEART trial. Cardiovasc Diabetol. 2017;16(1):130.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Russo I, Frangogiannis NG. Diabetes-associated cardiac fibrosis: cellular effectors, molecular mechanisms and therapeutic opportunities. J Mol Cell Cardiol. 2016;90:84–93.

    Article  CAS  PubMed  Google Scholar 

  33. de Cavanagh EM, Inserra F, Toblli J, Stella I, Fraga CG, Ferder L. Enalapril attenuates oxidative stress in diabetic rats. Hypertension. 2001;38:1130–6.

    Article  PubMed  Google Scholar 

  34. Ramalingam L, Menikdiwela K, LeMieux M, Dufour JM, Kaur G, Kalupahana N, et al. The renin angiotensin system, oxidative stress and mitochondrial function in obesity and insulin resistance. Biochim Biophys Acta Mol Basis Dis. 2017;1863(5):1106–14.

    Article  CAS  PubMed  Google Scholar 

  35. Jiang F, Liu GS, Dusting GJ, Chan EC. NADPH oxidase-dependent redox signaling in TGF-beta-mediated fibrotic responses. Redox Biol. 2014;2:267–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhou B, Tian R. Mitochondrial dysfunction in pathophysiology of heart failure. J Clin Invest. 2018;128:3716–26.

    Article  PubMed  PubMed Central  Google Scholar 

  37. •• Packer M. Autophagy-dependent and -independent modulation of oxidative and organellar stress in the diabetic heart by glucose-lowering drugs. Cardiovasc Diabetol. 2020;19:62. The author reviewed and underlined the effect of SGLT2 on cellular stress and autophagy by activating sirtuins 1 and AMPK. In addition, the enhanced activity of HIF-2α stimulates erythrocytosis and oxygen supply to the myocardium. Their action on nutrient deprivation pathways may give SGLT2 inhibitors the ability to attenuate oxidative stress improve heart function, and reduce cardiovascular events.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Qi Z, Wu D, Li M, Yan Z, Yang X, Ji N, et al. The pluripotent role of exosomes in mediating non-coding RNA in ventricular remodeling after myocardial infarction. Life Sci. 2020;254:117761.

    Article  CAS  PubMed  Google Scholar 

  39. Levine B, Kroemer G. Biological functions of autophagy genes: a disease perspective. Cell. 2019;176:11–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Fang EF, Scheibye-Knudsen M, Brace LE, Kassahun H, SenGupta T, Nilsen H, et al. Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction. Cell. 2014;157:882–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Dominic EA, Ramezani A, Anker SD, Verma M, Mehta N, Rao M. Mitochondrial cytopathies and cardiovascular disease. Heart. 2014;100:611–8.

    Article  CAS  PubMed  Google Scholar 

  42. Zak R, Rabinowitz M, Rajamanickam C, Merten S, Kwiatkowska-Patzer B. Mitochondrial proliferation in cardiac hypertrophy. Basic Res Cardiol. 1980;75:171–8.

    Article  CAS  PubMed  Google Scholar 

  43. Vásquez-Trincado C, García-Carvajal I, Pennanen C, Parra V, Hill JA, Rothermel BA, et al. Mitochondrial dynamics, mitophagy and cardiovascular disease. J Physiol. 2016;594:509–25. https://doi.org/10.1113/JP271301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. McDonnell E, Peterson BS, Bomze HM, Hirschey MD. SIRT3 regulates progression and development of diseases of aging. Trends Endocrinol Metab. 2015;26:486–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zhang J, Xiang H, Liu J, Chen Y, He R-R, Liu B. Mitochondrial sirtuin 3: new emerging biological function and therapeutic target. Theranostics. 2020;10:8315–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Javadov S, Escobales N. The role of SIRT3 in mediating cardioprotective effects of RAS inhibition on cardiac ischemia-reperfusion. J Pharm Pharm Sci. 2015;18:547–50.

    Article  PubMed  Google Scholar 

  47. de Cavanagh EM, Inserra F, Ferder L. Angiotensin II blockade: a strategy to slow ageing by protecting mitochondria? Cardiovasc Res. 2011;89:31–40.

    Article  PubMed  Google Scholar 

  48. Jing E, Emanuelli B, Hirschey MD, Boucher J, Lee KY, Lombard D, et al. Sirtuin-3 (Sirt3) regulates skeletal muscle metabolism and insulin signaling via altered mitochondrial oxidation and reactive oxygen species production. Proc Natl Acad Sci USA. 2011;108:14608–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Koentges C, Pfeil K, Schnick T, Wiese S, Dahlbock R, Cimolai MC, et al. SIRT3 deficiency impairs mitochondrial and contractile function in the heart. Basic Res Cardiol. 2015;110:136.

    Article  Google Scholar 

  50. Benjamin EJ, Blaha MJ, Chiuve SE, et al. Heart disease and stroke statistics-2017 update: a report from the American Heart Association. Circulation. 2017;135(10):e146-603.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. Massachusetts Medical Society; 2017;377:644–57.

  52. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–28.

    Article  CAS  PubMed  Google Scholar 

  53. Kosiborod M, Cavender MA, Fu AZ, Wilding JP, Khunti K, Holl RW, et al. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL study (comparative effectiveness of cardiovascular outcomes in new users of sodium-glucose cotransporter-2 inhibitors). Circulation. 2017;136:249–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. • Kosiborod M, Lam CSP, Kohsaka S, Kim DJ, Karasik A, Shaw J, et al. Cardiovascular events associated with SGLT-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL 2 study. J Am Coll Cardiol. 2018;71:2628–39. This real-life study confirms the reproducibility of the results obtained in cardiovascular trials with SGLT2 inhibition and the benefit vs. other glucose-lowering drugs.

    Article  CAS  PubMed  Google Scholar 

  55. Santulli G, Wang X, Mone P. Updated ACC/AHA/HFSA 2022 guidelines on heart failure: what is new? From epidemiology to clinical management. Eur Heart J Cardiovasc Pharmacother. 2022;8(5):e23–4.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Lee MMY, Brooksbank KJM, Wetherall K, Mangion K, Roditi G, Campbell RT, et al. Effect of empagliflozin on left ventricular volumes in patients with type 2 diabetes, or prediabetes, and heart failure with reduced ejection fraction (SUGAR-DM-HF). Circulation. 2021;143:516–25.

    Article  CAS  PubMed  Google Scholar 

  57. Nuffield Department of Population Health Renal Studies Group, SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists’ Consortium. Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials. Lancet. 2022. https://doi.org/10.1016/S0140-6736(22)02074-8.

    Article  Google Scholar 

  58. Verma S, Mazer CD, Yan AT, Mason T, Garg V, Teoh H, et al. Effect of empagliflozin on left ventricular mass in patients with type 2 diabetes mellitus and coronary artery disease: the EMPA-HEART CardioLink-6 randomized clinical trial. Circulation. 2019;140:1693–702.

    Article  PubMed  Google Scholar 

  59. Connelly KA, Zhang Y, Visram A, Advani A, Batchu SN, Desjardins JF, et al. Empagliflozin improves diastolic function in a nondiabetic rodent model of heart failure with preserved ejection fraction. JACC Basic Transl Sci. 2019;4:27–37.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Shi L, Zhu D, Wang S, Jiang A, Li F. Dapagliflozin attenuates cardiac remodeling in mice model of cardiac pressure overload. Am J Hypertens. 2019;32:452–933.

    Article  CAS  PubMed  Google Scholar 

  61. Verma S, Garg A, Yan AT, Gupta AK, Al-Omran M, Sabongui A, et al. Effect of empagliflozin on left ventricular mass and diastolic function in individuals with diabetes: an important clue to the EMPA-REG OUTCOME trial? Diabetes Care. 2016;39:e212–3.

    Article  PubMed  Google Scholar 

  62. Kang S, Verma S, Hassanabad AF, Teng G, Belke DD, Dundas JA, et al. Direct effects of empagliflozin on extracellular matrix remodelling in human cardiac myofibroblasts: novel translational clues to explain EMPA-REG OUTCOME results. Can J Cardiol. 2020;36:543–53.

    Article  PubMed  Google Scholar 

  63. Lee HC, Shiou YL, Jhuo SJ, Chang CY, Liu PL, Jhuang WJ, et al. The sodium-glucose co-transporter 2 inhibitor empagliflozin attenuates cardiac fibrosis and improves ventricular hemodynamics in hypertensive heart failure rats. Cardiovasc Diabetol. 2019;18:45.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Heerspink HJL, Perco P, Mulder S, Leierer J, Hansen MK, Heinzel A, et al. Canagliflozin reduces inflammation and fibrosis biomarkers: a potential mechanism of action for beneficial effects of SGLT2 inhibitors in diabetic kidney disease. Diabetologia. 2019;62:1154–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Leng W, Wu M, Pan H, Lei X, Chen L, Wu Q, et al. The SGLT2 inhibitor dapagliflozin attenuates the activity of ROS-NLRP3 inflammasome axis in steatohepatitis with diabetes mellitus. Ann Transl Med. 2019;7:429.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Li C, Zhang J, Xue M, Li X, Han F, Liu X, et al. SGLT2 inhibition with empagliflozin attenuates myocardial oxidative stress and fibrosis in diabetic mice heart. Cardiovasc Diabetol. 2019;18:15.

    Article  PubMed  PubMed Central  Google Scholar 

  67. • Lopaschuk GD, Verma S. Mechanisms of cardiovascular benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors: a state-of-the-art review. JACC Basic Transl Sci. 2020;5:632–449. This article reviews the potential mechanisms involved in the essential and unexpected results in cardiovascular protection found for SGLT2 inhibitors.

    Article  PubMed  PubMed Central  Google Scholar 

  68. • Zou R, Shi W, Qiu J, Zhou N, Du N, Zhou H, et al. Empagliflozin attenuates cardiac microvascular ischemia/reperfusion injury through improving mitochondrial homeostasis. Cardiovasc Diabetol. 2022;21:106. This article highlight the relevance of the improvement of mitochondrial function during SGLT2 inhibition on myocardium microvascular protection.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. Massachusetts Medical Society; 2019;381:1995–2008.

  70. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. Massachusetts Medical Society; 2020;383:1413–24.

  71. Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Böhm M, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. Massachusetts Medical Society; 2021;385:1451–61.

  72. Solomon SD, McMurray JJV, Claggett B, de Boer RA, DeMets D, Hernandez AF, et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. Massachusetts Medical Society; 2022;387:1089–98.

  73. Bhatt DL, Szarek M, Steg PG, Cannon CP, Leiter LA, McGuire DK, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med. Massachusetts Medical Society; 2021;384:117–28.

  74. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. Massachusetts Medical Society; 2019;380:347–57.

  75. Cannon CP, Pratley R, Dagogo-Jack S, Mancuso J, Huyck S, Masiukiewicz U, et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med. Massachusetts Medical Society; 2020;383:1425–35.

  76. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. Massachusetts Medical Society; 2019;380:2295–306.

  77. Bhatt DL, Szarek M, Pitt B, Cannon CP, Leiter LA, McGuire DK, et al. Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med. Massachusetts Medical Society; 2021;384:129–39.

  78. Heerspink HJL, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T, Hou F-F, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. Massachusetts Medical Society; 2020;383:1436–46.

  79. EMPA-KIDNEY Collaborative Group, Herrington WG, Staplin N, Wanner C, Green JB, Hauske SJ, et al. Empagliflozin in patients with chronic kidney disease. N Engl J Med. 2022.

  80. Ye Y, Bajaj M, Yang HC, Perez-Polo JR, Birnbaum Y. SGLT-2 inhibition with dapagliflozin reduces the activation of the Nlrp3/ASC inflammasome and attenuates the development of diabetic cardiomyopathy in mice with type 2 diabetes. Further augmentation of the effects with saxagliptin, a DPP4 inhibitor. Cardiovasc Drugs Ther. 2017;31:119–32. https://doi.org/10.1007/s10557-017-6725-2.

    Article  CAS  PubMed  Google Scholar 

  81. El-Daly M, Pulakazhi Venu VK, Saifeddine M, et al. Hyperglycaemic impairment of PAR2-mediated vasodilation: prevention by inhibition of aortic endothelial sodium-glucoseco-transporter-2 and minimizing oxidative stress. Vascul Pharmacol. 2018;109:56–71. https://doi.org/10.1016/j.vph.2018.06.006.

    Article  CAS  PubMed  Google Scholar 

  82. Uthman L, Li X, Baartscheer A, Schumacher CA, Baumgart P, Hermanides J, et al. Empagliflozin reduces oxidative stress through inhibition of the novel inflammation/NHE/[Na+]c/ROS-pathway in human endothelial cells. Biomed Pharmacother. 2022;146:112515. https://doi.org/10.1016/j.biopha.2021.112515.

    Article  CAS  PubMed  Google Scholar 

  83. Ferrannini E, Mark M, Mayoux E. Cardiovascular protection in the EMPA-REG OUTCOME trial: a ‘thrifty substrate’ hypothesis. Diabetes Care. 2016;39:1108–14.

    Article  PubMed  Google Scholar 

  84. Horton JL, Davidson MT, Kurishima C, et al. The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense. JCI Insight. 2019;4:12407. https://doi.org/10.1172/jci.insight.124079.

    Article  Google Scholar 

  85. Verma S, Rawat S, Ho KL, Wagg CS, Zhang L, Teoh H, et al. Empagliflozin increases cardiac energy production in diabetes: novel translational insights into the heart failure benefits of SGLT2 inhibitors. JACC Basic Transl Sci. 2018;3:575–87.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Hodrea J, Saeed A, Molnar A, Fintha A, Barczi A, Wagner LJ, et al. SGLT2 inhibitor dapagliflozin prevents atherosclerotic and cardiac complications in experimental type 1 diabetes. PLoS ONE. 2022;17(2):e0263285.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. • Mone P, Varzideh F, Jankauskas SS, Pansini A, Lombardi A, Frullone S, et al. SGLT2 inhibition via empagliflozin improves endothelial function and reduces mitochondrial oxidative stress: insights from frail hypertensive and diabetic patients. Hypertension. 2022;79:1633–43. https://doi.org/10.1161/HYPERTENSIONAHA.122.19586. The authors describe the endothelial function improvement associated with SGLT2 inhibition and oxidative stress reduction in endothelial cells.

    Article  CAS  PubMed  Google Scholar 

  88. Sugiyama S, Jinnouchi H, Kurinami N, Hieshima K, Yoshida A, Jinnouchi K, et al. The SGLT2 inhibitor dapagliflozin significantly improves the peripheral microvascular endothelial function in patients with uncontrolled type 2 diabetes mellitus. Intern Med. 2018;57:2147–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. González-Clemente JM, García-Castillo M, Gorgojo-Martínez JJ, Jiménez A, Llorente I, Matute E, et al. Beyond the glycaemic control of dapagliflozin: impact on arterial stiffness and macroangiopathy. Diabetes Ther. 2022;13:1281–98. https://doi.org/10.1007/s13300-022-01280-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Tanaka A, Shimabukuro M, Machii N, Teragawa H, Okada Y, Shima KR, et al. Effect of empagliflozin on endothelial function in patients with type 2 diabetes and cardiovascular disease: results from the multicenter, randomized, placebo-controlled, double-blind EMBLEM trial. Diabetes Care. 2019;42:e159–61.

    Article  CAS  PubMed  Google Scholar 

  91. Oliva RV, Bakris GL. Blood pressure effects of sodium-glucose co-transport 2 (SGLT2) inhibitors. J Am Soc Hypertens. 2014;8(5):330–9.

    Article  CAS  PubMed  Google Scholar 

  92. Bosch A, Ott C, Jung S, et al. How does empagliflozin improve arterial stiffness in patients with type 2 diabetes mellitus? Sub analysis of a clinical trial. Cardiovasc Diabetol. 2019;18(1):44.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Majewski C, Bakris GL. Blood pressure reduction: an added benefit of sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes. Diabetes Care. 2015;38(3):429–30.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Solini A, Giannini L, Seghieri M, et al. Dapagliflozin acutely improves endothelial dysfunction, reduces aortic stiffness and renal resistive index in type 2 diabetic patients: a pilot study. Cardiovasc Diabetol. 2017;16(1):138.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Wang CY, Chen CC, Lin MH, Su HT, Ho MY, Yeh JK, et al. TLR9 binding to beclin 1 and mitochondrial SIRT3 by a sodium-glucose co-transporter 2 inhibitor protects the heart from doxorubicin toxicity. Biology. 2020;9:369.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. D’Onofrio N, Sardu C, Trotta MC, Scisciola L, Turriziani F, Ferraraccio F, et al. Sodium-glucose co-transporter2 expression and inflammatory activity in diabetic atherosclerotic plaques: effects of sodium-glucose co-transporter2 inhibitor treatment. Mol Metab. 2021;54:101337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Sun N, Youle RJ, Finkel T. The mitochondrial basis of aging. Mol Cell. 2016;61(5):654–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Hebert AS, Dittenhafer-Reed KE, Yu W, et al. Calorie restriction and SIRT3 trigger global reprogramming of the mitochondrial protein acetylome. Mol Cell. 2013;49(1):186–99.

    Article  CAS  PubMed  Google Scholar 

  99. Wang Y. Molecular links between caloric restriction and Sir2/ SIRT1 activation. Diabetes Metab J. 2014;38(5):321–9.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Noriega LG, Feige JN, Canto C, et al. CREB and ChREBP oppositely regulate SIRT1 expression in response to energy availability. EMBO Rep. 2011;12(10):1069–76.

    Article  CAS  PubMed Central  Google Scholar 

  101. Penke M, Larsen PS, Schuster S, et al. Hepatic NAD salvage pathway is enhanced in mice on a high-fat diet. Mol Cell Endocrinol. 2015;412:65–72.

    Article  CAS  PubMed  Google Scholar 

  102. Cantó C, Gerhart-Hines Z, Feige JN, et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature. 2009;458(7241):1056–60.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Yang X, Liu Q, Li Y, et al. The diabetes medication canagliflozin promotes mitochondrial remodelling of adipocyte via the AMPK-Sirt1-Pgc-1α signalling pathway. Adipocyte. 2020;9(1):484–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Hariharan N, Maejima Y, Nakae J, et al. Deacetylation of FoxO by Sirt1 plays an essential role in mediating starvation-induced autophagy in cardiac myocytes. Circ Res. 2010;107:1470–82. https://doi.org/10.1161/CIRCRESAHA.110.227371.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Morales CR, Pedrozo Z, Lavandero S, Hill JA. Oxidative stress and autophagy in cardiovascular homeostasis. Antioxid Redox Signal. 2014;20:507–18. https://doi.org/10.1089/ars.2013.5359. PMID: 23641894.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. • Kumar AA, Kelly DP, Chirinos JA. Mitochondrial dysfunction in heart failure with preserved ejection fraction. Circulation. 2019;139:1435–50. https://doi.org/10.1161/CIRCULATIONAHA.118.036259. The authors describe heart failure with preserved ejection fraction syndrome and highlight mitochondrial abnormalities contributing to it. They review the complexity of mitochondria’s biology and the possibility that mitochondrial function and abnormalities could be a potential therapeutic target.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Hahn VS, Knutsdottir H, Luo X, et al. Myocardial gene expression signatures in human heart failure with preserved ejection fraction. Circulation. 2021;143:120–34. https://doi.org/10.1161/CIRCULATIONAHA.120.050498. PMID: 33118835.

    Article  CAS  PubMed  Google Scholar 

  108. Upadhya B, Taffet GE, Cheng CP, Kitzman DW. Heart failure with preserved ejection fraction in the elderly: scope of the problem. J Mol Cell Cardiol. 2015;83:73–87. https://doi.org/10.1016/j.yjmcc.2015.02.025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Packer M. Cardioprotective effects of sirtuin-1 and its downstream effectors: potential role in mediating the heart failure benefits of SGLT2 (sodium-glucose cotransporter 2) inhibitors. Circ Heart Fail. 2020;13:e007197. https://doi.org/10.1161/CIRCHEARTFAILURE.120.007197.

    Article  CAS  PubMed  Google Scholar 

  110. Swe MT, Thongnak L, Jaikumkao K, et al. Dapagliflozin not only improves hepatic injury and pancreatic endoplasmic reticulum stress, but also induces hepatic gluconeogenic enzymes expression in obese rats. Clin Sci (Lond). 2019;133:2415–30. https://doi.org/10.1042/CS20190863.

    Article  CAS  PubMed  Google Scholar 

  111. Zhazykbayeva S, Pabel S, Mugge A, et al. The molecular mechanisms associated with the physiological responses to inflammation and oxidative stress in cardiovascular diseases. Biophys Rev. 2020;12:947–68. https://doi.org/10.1007/s12551-020-00742-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Baker HE, Kiel AM, Luebbe ST, et al. Inhibition of sodium-glucose cotransporter-2 preserves cardiac function during regional myocardial ischemia independent of alterations in myocardial substrate utilization. Basic Res Cardiol. 2019;114:25. https://doi.org/10.1007/s00395-019-0733-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Rojas-Morales P, Tapia E, Pedraza-Chaverri J. Beta-hydroxybutyrate: a signaling metabolite in starvation response? Cell Signal. 2016;28:917–23. https://doi.org/10.1016/j.cellsig.2016.04.005.

    Article  CAS  PubMed  Google Scholar 

  114. Youm YH, Nguyen KY, Grant RW, et al. The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med. 2015;21:263–9. https://doi.org/10.1038/nm.3804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Lopaschuk GD, Karwi QG, Tian R, et al. Cardiac energy metabolism in heart failure. Circ Res. 2021;128:1487–513. https://doi.org/10.1161/CIRCRESAHA.121.318241.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Packer M. Mechanisms leading to differential hypoxia inducible factor signaling in the diabetic kidney: modulation by SGLT2 inhibitors and hypoxia mimetics. Am J Kidney Dis. 2021;77:280–6. https://doi.org/10.1053/j.ajkd.2020.04.016.

    Article  CAS  PubMed  Google Scholar 

  117. Chen R, Xu M, Hogg RT, et al. The acetylase/deacetylase couple CREB-binding protein/sirtuin 1 controls hypoxiainducible factor 2 signaling. J Biol Chem. 2012;287:30800–11. https://doi.org/10.1074/jbc.M111.244780.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Mazer CD, Hare GMT, Connelly PW, et al. Effect of empagliflozin on erythropoietin levels, iron stores, and red blood cell morphology in patients with type 2 diabetes mellitus and coronary artery disease. Circulation. 2020;141:704–7. https://doi.org/10.1161/CIRCULATIONAHA.119.044235.

    Article  PubMed  Google Scholar 

  119. Inzucchi SE, Zinman B, Fitchett D, et al. How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME trial. Diabetes Care. 2018;41:356–63. https://doi.org/10.2337/dc17-1096.

    Article  CAS  PubMed  Google Scholar 

  120. Verma S, Mazer CD, Bhatt DL, et al. Empagliflozin and cardiovascular outcomes in patients with type 2 diabetes and left ventricular hypertrophy: a subanalysis of the EMPAREG OUTCOME trial. Diabetes Care. 2019;42:e42-4. https://doi.org/10.2337/dc18-1959.

    Article  CAS  PubMed  Google Scholar 

  121. Wei W, Rao F, Liu F, et al. Involvement of Smad3 pathway in atrial fibrosis induced by elevated hydrostatic pressure. J Cell Physiol. 2018;233:4981–9. https://doi.org/10.1002/jcp.26337.

    Article  CAS  PubMed  Google Scholar 

  122. Han L, Tang Y, Li S, et al. Protective mechanism of SIRT1 on Hcy-induced atrial fibrosis mediated by TRPC3. J Cell Mol Med. 2020;24:488–510. https://doi.org/10.1111/jcmm.14757.

    Article  CAS  PubMed  Google Scholar 

  123. Sweeney M, Corden B, Cook SA. Targeting cardiac fibrosis in heart failure with preserved ejection fraction: mirage or miracle? EMBO Mol Med. 2020;12:e10865. https://doi.org/10.15252/emmm.201910865.

  124. Zeng H, Chen JX. Sirtuin 3, endothelial metabolic reprogramming, and heart failure with preserved ejection fraction. J Cardiovasc Pharmacol. 2019;74:315–23. https://doi.org/10.1097/FJC.0000000000000719.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Mishra S, Kass DA. Cellular and molecular pathobiology of heart failure with preserved ejection fraction. Nat Rev Cardiol. 2021;18:400–23. https://doi.org/10.1038/s41569-020-00480-6.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Wang CY, Chen CC, Lin MH, et al. TLR9 binding to beclin 1 and mitochondrial SIRT3 by a sodium-glucose co-transporter 2 inhibitor protects the heart from doxorubicin toxicity. Biology (Basel). 2020;9:369. https://doi.org/10.3390/biology9110369.

    Article  CAS  PubMed  Google Scholar 

  127. D’Amario D, Migliaro S, Borovac JA, et al. Microvascular dysfunction in heart failure with preserved ejection fraction. Front Physiol. 2019;10:1347. https://doi.org/10.3389/fphys.2019.01347.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Hamdani N, Costantino S, Mugge A, et al. Leveraging clinical epigenetics in heart failure with preserved ejection fraction: a call for individualized therapies. Eur Heart J. 2021;42:1940–58. https://doi.org/10.1093/eurheartj/ehab197.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Nambu H, Takada S, Fukushima A, et al. Empagliflozin restores lowered exercise endurance capacity via the activation of skeletal muscle fatty acid oxidation in a murine model of heart failure. Eur J Pharmacol. 2020;866:172810. https://doi.org/10.1016/j.ejphar.2019.172810.

    Article  CAS  PubMed  Google Scholar 

  130. Spertus JA, Birmingham MC, Nassif M, Damaraju CV, Abbate A, Butler J, et al. The SGLT2 inhibitor canagliflozin in heart failure: the CHIEF-HF remote, patient-centered randomized trial. Nat Med. 2022;28:809–13. https://doi.org/10.1038/s41591-022-01703-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. •• Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Böhm M, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021;385:1451–61. https://doi.org/10.1056/NEJMoa2107038. This trial was one of the most challenging investigations of SGLT2 inhibitors on cardiovascular protection and prevention of events in patients with heart failure. The EMPEROR Preserved trial verified that empagliflozin could reduce the combined endpoint of cardiovascular death or hospitalization for heart failure in patients with heart failure and a preserved ejection fraction, with or without diabetes.

  132. Sundaresan NR, Vasudevan P, Zhong L, et al. The sirtuin SIRT6 blocks IGF-Akt signaling and development of cardiac hypertrophy by targeting c-Jun. Nat Med. 2012;18:1643–50. https://doi.org/10.1038/nm.2961.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. •• Packer M. Differential pathophysiological mechanisms in heart failure with a preserved ejection fraction in diabetes. JACC Heart Fail. 2021;9:535–49. https://doi.org/10.1016/j.jchf.2021.05.019. Dr. Packer describes the various mechanisms involved in heart failure and the pathways that mediate its development. It is to highlight that makes focus on hyperinsulinemia and its consequences, especially epicardial adipose tissue expansion and the resulting proinflammatory adipocytokines that are causes of coronary microcirculatory dysfunction and myocardial inflammation, and fibrosis. The author also reviews the indirect and direct favorable effects that SGLT2 inhibitors have on epicardial adipose tissue, reducing it and another myocardial inflammatory process.

  134. Cingolani HE, Ennis IL. Sodium-hydrogen exchanger, cardiac overload, and myocardial hypertrophy. Circulation. 2007;115:1090–100. https://doi.org/10.1161/CIRCULATIONAHA.106.626929.

    Article  PubMed  Google Scholar 

  135. Mraiche F, Oka T, Gan XT, et al. Activated NHE1 is required to induce early cardiac hypertrophy in mice. Basic Res Cardiol. 2011;106:603–16. https://doi.org/10.1007/s00395-011-0161-4.

    Article  CAS  PubMed  Google Scholar 

  136. Zuurbier CJ, Baartscheer A, Schumacher CA, et al. SGLT2 inhibitor empagliflozin inhibits the cardiac Na+/H+ exchanger 1: persistent inhibition under various experimental conditions. Cardiovasc Res. 2021;117:2699–701. https://doi.org/10.1093/cvr/cvab129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Trum M, Riechel J, Wagner S. Cardioprotection by SGLT2 inhibitors – does it all come down to Na+ ? Int J Mol Sci. 2021;22:7976. https://doi.org/10.3390/ijms22157976.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Cappetta D, De Angelis A, Ciuffreda LP, et al. Amelioration of diastolic dysfunction by dapagliflozin in a non-diabetic model involves coronary endothelium. Pharmacol Res. 2020;157:104781. https://doi.org/10.1016/j.phrs.2020.104781.

    Article  CAS  PubMed  Google Scholar 

  139. Han Y, Cho YE, Ayon R, et al. SGLT inhibitors attenuate no-dependent vascular relaxation in the pulmonary artery but not in the coronary artery. Am J Physiol Lung Cell Mol Physiol. 2015;309:L1027–36. https://doi.org/10.1152/ajplung.00167.2015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Nassif ME, Qintar M, Windsor SL, et al. Empagliflozin effects on pulmonary artery pressure in patients with heart failure: results from the EMBRACE-HF trial. Circulation. 2021;143:1673–86. https://doi.org/10.1161/CIRCULATIONAHA.120.052503.

    Article  CAS  PubMed  Google Scholar 

  141. Mullens W, Martens P. Empagliflozin-induced changes in epicardial fat: the centerpiece for myocardial protection? JACC Heart Fail. 2021;9:590–3. https://doi.org/10.1016/j.jchf.2021.05.006.

    Article  PubMed  Google Scholar 

  142. Oikonomou EK, Antoniades C. The role of adipose tissue in cardiovascular health and disease. Nat Rev Cardiol. 2019;16:83–99. https://doi.org/10.1038/s41569-018-0097-6.

    Article  PubMed  Google Scholar 

  143. Payne GA, Kohr MC, Tune JD. Epicardial perivascular adipose tissue as a therapeutic target in obesity-related coronary artery disease. Br J Pharmacol. 2012;165:659–69. https://doi.org/10.1111/j.1476-5381.2011.01370.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Putko BN, Wang Z, Lo J, et al. Circulating levels of tumor necrosis factor-alpha receptor 2 are increased in heart failure with preserved ejection fraction relative to heart failure with reduced ejection fraction: evidence for a divergence in pathophysiology. PLoS ONE. 2014;9:e99495. https://doi.org/10.1371/journal.pone.0099495.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Miao K, Zhou L, Ba H, et al. Transmembrane tumor necrosis factor alpha attenuates pressure-overload cardiac hypertrophy via tumor necrosis factor receptor 2. PLoS Biol. 2020;18:e3000967. https://doi.org/10.1371/journal.pbio.3000967.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Mizuta E, Kokubo Y, Yamanaka I, et al. Leptin gene and leptin receptor gene polymorphisms are associated with sweet preference and obesity. Hypertens Res. 2008;31:1069–77. https://doi.org/10.1291/hypres.31.1069.

    Article  CAS  PubMed  Google Scholar 

  147. Faxén UL, Hage C, Andreasson A, et al. HFpEF and HFrEF exhibit different phenotypes as assessed by leptin and adiponectin. Int J Cardiol. 2017;228:709–16. https://doi.org/10.1016/j.ijcard.2016.11.194.

    Article  PubMed  Google Scholar 

  148. Tian G, Luo C, Liu L. Epicardial adipose tissue-derived leptin induce MMPS/TIMPS imbalance and promote cardiac fibrosis through JAK2/ROS/NA/K-ATPase/ERK1/2 signaling pathway in high fat diet-induced obese rats. J Am Coll Cardiol. 2022;79(9 Suppl):1544. https://doi.org/10.1016/S0735-1097(22)02535-9.

    Article  Google Scholar 

  149. Vickers SP, Cheetham SC, Headland KR, et al. Combination of the sodium-glucose cotransporter-2 inhibitor empagliflozin with orlistat or sibutramine further improves the body-weight reduction and glucose homeostasis of obese rats fed a cafeteria diet. Diabetes Metab Syndr Obes. 2014;7:265–75. https://doi.org/10.2147/DMSO.S58786.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by grants from the Research and Technology Council of Cuyo University (SECyT), Mendoza, Argentina, and from the National Agency for the Promotion of Research, Technological Development and Innovation ANPCyT FONCyT (Grant no. PICT 2020-Serie A- 4000).

Author information

Authors and Affiliations

  1. Laboratorio de Farmacología Experimental Básica y Traslacional, Área de Farmacología, Departamento de Patología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina

    Raúl Lelio Sanz, Sebastián García Menéndez, Luciana Mazzei & Walter Manucha

  2. Universidad Maimónides, Ciudad Autónoma de Buenos Aires, Argentina

    Felipe Inserra, León Ferder & Walter Manucha

  3. Instituto de Medicina y Biología Experimental de Cuyo, Consejo Nacional de Investigación Científica y Tecnológica (IMBECU-CONICET), Mendoza, Argentina

    Sebastián García Menéndez & Luciana Mazzei

Authors
  1. Raúl Lelio Sanz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Felipe Inserra
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sebastián García Menéndez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Luciana Mazzei
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. León Ferder
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Walter Manucha
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Walter Manucha.

Ethics declarations

Conflict of Interest

Felipe Inserra: Consultancy and honoraria: Astra Zeneca, Boehringer Ingelheim, Novo Nordisk.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sanz, R.L., Inserra, F., García Menéndez, S. et al. Metabolic Syndrome and Cardiac Remodeling Due to Mitochondrial Oxidative Stress Involving Gliflozins and Sirtuins. Curr Hypertens Rep 25, 91–106 (2023). https://doi.org/10.1007/s11906-023-01240-w

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11906-023-01240-w

Keywords

Search

Navigation