Direct cardial effects and mechanisms of cardiovascular action of gliflosins

Cover Page


Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract

The literature review is devoted to the study of the mechanisms of the cardioprotective action of a new class of glucose-lowering drugs glyflozins, which inhibit the joint transport of sodium and glucose in the proximal renal tubules. Favorable changes in ion transport in cardiomyocytes with the use of these drugs are considered. The inhibition of the activity of the sodium-hydrogen exchanger (NHE) was found, followed by a decrease in the activity of Na+/ Ca2+ exchange on the mitochondrial membranes of the cardiomyocytes, which leads to a decrease in the concentration of Ca2+ in the cytoplasm with a simultaneous increase in mitochondria. This initiates a number of intracellular signaling cascades that contribute to the optimization of mitochondrial homeostasis. The use of glyflozins, apparently, provides a balance between the fusion and fission of mitochondria, which determines the bioenergetic adaptation of the cell to the state of intracellular metabolism, weakens the development of the inflammatory response, fibrosis and oxidative stress in the myocardium, which are activated under conditions of diabetes mellitus. The point of view is discussed, according to which the mechanism of anti-inflammatory action of glyflozins is associated with inhibition of the activity of the NLRP3 inflammasome, which contributes to the progression of myocardial dysfunction and subsequent chronic heart failure. The results of clinical trials and experimental data on the beneficial effect of glyflozins in the development of various phenotypes of heart failure with reduced and preserved ejection fraction are analyzed. The assumption is substantiated about the prospects for wider use of these hypoglycemic drugs in heart failure, which is not limited to diabetes mellitus. The assumptions made require further experimental and clinical studies.

Full Text

Restricted Access

About the authors

Yakov F. Zverev

Altai State Medical University

Author for correspondence.
Email: zveryasha@mail.ru
ORCID iD: 0000-0002-8101-103X
SPIN-code: 4520-7720

MD, PhD, Dsci (Medicine), Professor. Tht Deparment of Pharmacology, Altai State Medical University

Russian Federation, 40 Lenina str., 656038, Barnaul

Anna Y. Rykunova

Barnaul Law Institute

Email: zveranna@mail.ru
ORCID iD: 0000-0002-5889-7071
SPIN-code: 4355-8205

PhD, Cand. Sci. (Med.)

Russian Federation, Barnaul

References

  1. Filippatos TD, Liontos A, Papakitsou I, Elisaf MS. SGLT2 inhibitors and cardioprotection: a matter of debate and multiple hypothesis. Postgrad Med. 2019;131(2):82–88. doi: 10.1080/00325481.2019.1581971
  2. Packer M. Activation and inhibition of sodium-hydrogen exchanger is a mechanism that links the pathophysiology and treatment of diabetes mellitus with that of heart failure. Circulation. 2017;136(16): 1548–1559. doi: 10.1161/CIRCULATIONAHA.117.030418
  3. Arow M, Woldman M, Yadin D, et al. Sodium-glucose cotransporter 2 inhibitor Dapagliflozin attenuates diabetic cardiomyopathy. Cardiovasc Diabetol. 2020;19(1):7. doi: 10.1186/s12933-019-0980-4
  4. Maejima Y. SGLT2 inhibitors play a salutary role in heart failure via modulation of the mitochondrial function. Front Cardiovasc Med. 2020;6:186. doi: 10.3389/fcvm.2019.00186
  5. Anzawa R, Bernard M, Tamareille S, et al. Intracellular sodium increase and susceptibility to ischaemia in hearts from type 2 diabetic db/db mice. Diabetologia. 2006;49:598–606. doi: 10.1007/s00125-005-0091-5
  6. Prasad V, Lorenz J, Miller M, et al. Loss of NHE1 activity leads to reduced oxidative stress in heart and mitigates high-fat diet-induced myocardial stress. J Mol Cell Cardiol. 2013;65:33–42. doi: 10.1016/j.yjmcc.2013.09.013
  7. Baartscheer A, Schumacher CA, Wust RC, et al. Empagliflozin decreases myocardial cytoplasmic Na(+) through inhibition of the cardiac Na(+)/H(+) exchanger in rats and rabbits. Diabetologia. 2017;60(3):568–573. doi: 10.1007/s00125-016-4134-x
  8. Durak A, Olgar Y, Degirmenci S, et al. A SGLT2 inhibitor dapagliflozin suppresses prolonged ventricular-repolarization through augmentation of mitochondrial function in insulin-resistant metabolic syndrome rats. Cardiovasc Diabetol. 2018;17(1):144. doi: 10.1186/s12933-018-0790-0
  9. Habibi J, Aroor AR, Sowers JR, et al. Sodium glucose transporter 2 (SGLT2) inhibition with empagliflozin improves cardiac diastolic function in a female rodent model of diabetes. Cardiovasc Diabetol. 2017;16(1):9. doi: 10.1186/s12933-016-0489-z
  10. Voekl J, Lin Y, Alesutan J, et al. Sgk1 sensitivity of Na(+)/H(+) exchanger activity and cardiac remodeling following pressure overload. Basic Res Cardiol. 2012;107:236. doi: 10.1007/s00395-011-0236-2
  11. Uthman L, Baartscheer A, Schumacher CA, et al. Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na(+)/H(+) exchanger, lowering of cytosolic Na(+) and vasodilation. Diabetologia. 2018;61(3):722–726. doi: 10.1007/s00125-017-4509-7
  12. Shao Q, Meng L, Lee S, et al. Empagliflozin, a sodium glucose co-transporter-2 inhibitor, alleviates atrial remodeling and improves mitochondrial function in high-fat diet/streptozotocin-induced diabetic rats. Cardiovasc Diabetol. 2019;18(1):165. doi: 10.1186/s12933-019-0964-4
  13. Sabatino J, De Rosa S, Tamme L, et al. Empagliflozin prevents doxorubicin-induced myocardial dysfunction. Cardiovasc Diabetol. 2020;19:66. doi: 10.1186/s12933-020-01040-5
  14. Patrushev MV, Vinogradova EN, Kamenski PA, Mazunin IO. Mitochondrial fission and fusion. Biochemistry (Moscow). 2015;80(11):1673–1682. (In Russ.) doi: 10.1134/S0006297915110061
  15. Sciarretta S, Maejima Y, Zablocky D, Sadoshima J. The role of autophagy in the heart. Annu Rev Physiol. 2018;80:1–26. doi: 10.1146/annurev-physiol-021317-121427
  16. Chen Y, Liu Y, Dorn GW. II. Mitochondrial fusion is essential for organelle function and cardiac homeostasis. Circ Res. 2011;109(12):1327–1331. doi: 10.1161/CIRCRESAHA.111.258723
  17. Yaribeygi H, Atkin SL, Sanebkar A. Mitochondrial dysfunction in diabetes and the regulatory roles of antidiabetic agents on the mitochondrial function. J Cell Physiol. 2019;234(6):8402–8410. doi: 10.1002/jcp.27754
  18. Anderson EJ, Kypson AP, Rodriguez E, et al. Substrate specific derangements in mitochondrial metabolism and redox balance in the atrium of the type 2 diabetic human heart. J Am Coll Cardiol. 2009;54(20):1891–1898. doi: 10.1016/j.jacc.2009.07.031
  19. Kanaan GN, Patten DA, Redpath CJ, Harper ME. Atrial fibrillation is associated with impaired atrial mitochondrial energetics and supercomplex formation in adults with type 2 diabetes. Can J. Diab. 2019;43:(67–75): e1. doi: 10.1016/j.jcjd.2018.05.007
  20. Yurista SR, Silljé HHW, Rienstra M, et al. Sodium-glucose co-transporter 2 inhibition as a mitochondrial therapy for atrial fibrillation in patients with diabetes? Cardiovasc Diabetol. 2020;19:5. doi: 10.1186/s12933-019-0984-0
  21. Takagi S, Li J, Takagi Y, et al. Ipragliflozin improves mitochondrial abnormalities in renal tubules induced by a high-fat diet. J Diabetes Invest. 2018;9(5):1025–1032. doi: 10.1111/jdi.12802
  22. Mizuno M, Kuno A, Yano T, et al. Empagliflozin normalizes the size and number of mitochondria and prevents reduction in mitochondrial size after myocardial infarction in diabetic hearts. Physiol Rep. 2018;6(12): e13741. doi: 10.14814/phy2.13741
  23. Packer M. Autophagy-dependent and -independent modulation of oxidative and organellar stress in diabetic heart by glucose-lowering drugs. Cardiovasc Diabetol. 2020;19:62. doi: 10.1186/s12933-020-01041-4
  24. Weir HJ, Yao P, Huynh FK, et al. Dietary restriction and AMPK increase lifespan via mitochondrial network and peroxisome remodeling. Cell Metab. 2017;26(6):884–896.e5. doi: 10.1016/j.cmet.2017.09.024
  25. Packer M. Interplay of adenosine monophosphate-activated protein kinase/sirtuin-1 activation and sodium influx inhibition mediates the renal benefits of sodium-glucose co-transporter-2 inhibitors type 2 diabetes: A novel conceptual framework. Diabetes Obes Metab. 2020;22(5):734–742. doi: 10.1111/dom.13961
  26. Zhou H, Wang S, Zhu P, et al. Empagliflozin rescues diabetic myocardial microvascular injury via AMPK-mediated inhibition of mitochondrial fission. Redox Biol. 2018;15:335–346. doi: 10.1016/j.redox.2017.12.019
  27. Mancini SJ, Boyd D, Katwan OJ, et al. Canagliflozin inhibits interleukin-1β-stimulated cytokine and chemokine secretion in vascular endothelial cells by AMP-activated protein kinase-dependent and -independent mechanisms. Sci Rep. 2018;8(1):5276. doi: 10.1038/s41598-018-23420-4
  28. Hawley SA, Fords RJ, Smith BK, et al. The Na+/glucose cotransporter inhibitor canagliflozin activates AMPK by inhibiting mitochondrial function and increasing cellular AMP levels. Diabetes. 2016;65(9):2784–2794. doi: 10.2337/db16-0058
  29. Lu Q, Liu J, Li X, et al. Empagliflozin attenuates ischemia and reperfusion injury through LKB1/AMPK signaling pathway. Mol Cell Endocrinol. 2019;501:110642. doi: 10.1016/j.mce.2019.110642
  30. 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. 2019;133(23):2415–2430. doi: 10.1042/CS20190863
  31. Aragón-Herrera A, Feijóo-Bandin S, Otero Santiago M, et al. Empagliflozin reduces the levels of CD36 and cardiotoxic lipids while improving autophagy in the hearts of Zucker diabetic fatty rats. Biochem Pharmacol. 2019;170:113677. doi: 10.1016/j.bcp.2019.113677
  32. 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(6):632–644. doi: 10.1016/j.jacbts.2020.02.004
  33. Tokmachev RE, Budnevsky AV, Kravchenko AYa. The role of inflammation in the pathogenesis of chronic heart failure. Therapeutic archive. 2016;88(9):106–110. (In Russ.) doi: 10.17116/terarkh2016889106-119
  34. Iannantuoni F, de Marañon AM, Diaz-Morales N, et al. The SGLT2 inhibitor empagliflozin ameliorates the inflammatory profile in type 2 diabetic patients and promotes an antioxidant response in leukocytes. J Clin Med. 2019;8(11):1814. doi: 10.3390/jcm811814
  35. Heerspink HJL, Perco P, Mulder S, 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(7):1154–1166. doi: 10.1007/s00125-019-4859-4
  36. Leng W, Wu M, Pan H, et al. The SGLT2 inhibitor dapagliflozin attenuates the activity of ROS-NLRP3 inflammasome axis in steatohepatitis with diabetes mellitus. Ann Transl Med. 2019;7(18):429. doi: 10.21037/atm.2019.09.03
  37. Lee TM, Chang NC, Lin SZ. Dapagliflozin, a selective SGLT2 inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts. Free Radic Biol Med. 2017;104:298–310. doi: 10.1016/j.freeradbiomed.2017.01.035
  38. Kang SVS, Teng G, Belka D, et al. Direct effects of empagliflozin on extracellular matrix remodeling in human cardiac fibroblasts: Novel translational clues to explain EMPA-REG OUTCOME results. Can J Cardiol. 2020;36(4):543–553. doi: 10.1016/j.cica.2019.08.033
  39. Li C, Zhang J, Xue M, et al. SGLT2 inhibition with empagliflozin attenuates myocardial oxidative stress and fibrosis in diabetic mice heart. Cardiovasc Diabetol. 2019;18(1):15. doi: 10.1186/s12933-019-0816-2
  40. Lin B, Koibuchi N, Hasegawa Y, et al. Glycemic control with empagliflozin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injury and cognitive dysfunction in obese and type 2 diabetic mice. Cardiovasc Diabetol. 2014;13:148. doi: 10.1186/s12933-014-0148-1
  41. Kusaka H, Koibuchi N, Hasegawa Y, et al. Empagliflozin lessened cardiac injury and reduced visceral adipocyte hypertrophy in prediabetic rats with metabolic syndrome. Cardiovasc Diabetol. 2016;15(1):157. doi: 10.1186/s12933-016-0473-7
  42. Bonnet F, Scheen AJ. Effects of SGLT2 inhibitors on systemic and tissue low-grade inflammation: the potential contribution to diabetes complications and cardiovascular disease. Diabetes Metab. 2018;44(6):457–464. doi: 10.1016/j.diabet.2018.09.005
  43. Kuvacheva NV, Morgun AV, Hilazheva ED, et al. Inflammasomes forming: new mechanisms of intercellular interactions regulation and secretory activity of the cells. Siberian medical review. 2013;(83):3–10. (In Russ.) doi: 10.17116/terarkh2016889106-110
  44. Bae HR, Kim DH, Park MH, et al. beta-Hydroxybutyrate suppresses inflammasome formation by ameliorating endoplasmic reticulum stress via AMPK activation. Oncotarget. 2016;7(41): 66444–66454. doi: 10.18632/oncotarget.12119
  45. Ye Y, Bajaj M, Yang H-C, et al. SGLT2-2 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(2):119–132. doi: 10.1007/s10557-017-6725-2
  46. Inoue M-K, Matsunaga Y, Nakatsu Y, et al. Possible involvement of normalized Pin 1 expression level and AMPK activation in the molecular mechanisms underlying renal protective effects of SGLT2 inhibitors in mice. Diabetol Metab Syndr. 2019;11:57. doi: 10.1186/s13098-019-0454-6
  47. Byrne NJ, Matsumura N, Maayah ZH, et al. Empagliflozin blunts worsening cardiac dysfunction associated with reduced NLRP3 (nucleotide-binding domain-like receptor protein 3) inflammasome activation in heart failure. Circ Heart Fail. 2020;13(1): e006277. doi: 10.1161/CIRCHEARTFAILURE.119.006277
  48. Youm YH, Nguyen KY, Grant RW, et al. The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med. 2015;21:263–269. doi: 10.1038/nm.3804
  49. Zhou B, Tian R. Mitochondrial dysfunction in pathophysiology of heart failure. J Clin Invest. 2018;128(9):3716–3726. doi: 10.1172/JCI120849
  50. Lee T-I, Chen Y-C, Lin Y-K, et al. Empagliflozin attenuates myocardial sodium and calcium dysregulation and reverses cardiac remodeling in streptozotocin-induced diabetes rats. Int J Mol Sci. 2019;20(7):1680. doi: 10.3390/ijms20071680
  51. Zenkov NK, Kolpakov AR, Menshchikova EB. Keap1/nrf2/ARE redox-sensitive system as a phagmacological target in cardiovascular diseases. The Siberian scientific medical journal. 2015;35(5): 5–25. (In Russ.)
  52. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381:1995–2008. doi: 10.1056/NEJMoa1911303
  53. Kaplinsky E. DAPA-HF trial: dapagliflozin evolves from a glucose-lowering agent to a therapy for heart failure. Drugs in Context. 2020;9:2019-11-3. doi: 10.7573/dic.2019-11-3
  54. Packer M. Lessons learned from DAPA-HF trial concerning the mechanisms of benefit of SGLT2 inhibitors on heart failure events in the context of other large-scale trials nearing completion. Cardiovasc Diabetol. 2019;18:129. doi: 10.1186/s12933-019-0938-6
  55. Kobalava ZhD, Kiyakbaev GK. Type 2 diabetes and cardiovascular complications: is it possible to improve prognosis by glucose lowering therapy? Russian journal of cardiology. 2018;23(8):79–91. (In Russ.) doi: 10.15829/1560-4071-2018-8-79-91
  56. Rossiiskoe kardiologicheskoe obshchestvo. Klinicheskie rekomendatsii. Khronicheskaya serdechnaya nedostatochnost’ (KHSN). Moscow: Rossiiskoe kardiologicheskoe obshchestvo, 2020. 183 p. (In Russ.)
  57. Bouthoorn S, Valstar GB, Gohar A, et al. The prevalence of left ventricular diastolic dysfunction and heart failure with preserved ejection fraction in men and women with type 2 diabetes: a systematic review and meta-analysis. Diab Vasc Dis Res. 2018;15(6): 477–493. doi: 10.1177/1479164118787415
  58. Verma S, Garg A, Yan AT, 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(12): e212–e213. doi: 10.2337/dc16-1312
  59. Matsutani D, Sakamoto M, Kayama Y, et al. Effect of canagliflozin on left ventricular diastolic function in patients with type 2 diabetes. Cardiovasc Diabetol. 2018;17(1):73. doi: 10.1186/s12933-018-0717-9
  60. Sakai T, Miura S. Abstract 17041: effect of sodium-glucose cotransporter 2 inhibitor on vascular endothelial function in patients with heart failure with preserved ejection fraction (HFpEF). Circulation. 2018;136: A17041.
  61. Soga F, Tanaka H, Tatsumi K, et al. Impact of dapagliflozin on left ventricular diastolic function of patients with type 2 diabetic mellitus with chronic heart failure. Cardiovasc Diabetol. 2018;17(1):132. doi: 10.1186/s12933-018-0775-z
  62. Tanaka H, Soga F, Tatsumi K, et al. Positive effect of dapagliflozin on left ventricular longitudinal function for type 2 diabetic mellitus patients with chronic heart failure. Cardiovasc Diabetol. 2020;19(1):6. doi: 10.1186/s12933-019-0985-z
  63. Verma S, Mazer CD, Yan AT, 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(21):1693–1702. doi: 10.1161/CIRCULATIONAHA.119.042375
  64. Hwang I-C, Cho G-Y, Yoon YE, et al. Different effects of SGLT2 inhibitors according to the presence and types of heart failure in type 2 diabetic patients. Cardiovasc Diabetol. 2020;19(1):69. doi: 10.1186/s12933-020-01042-3
  65. Lee SJ, Lee KH, Oh HG, et al. Effect of sodium-glucose cotransporter 2 inhibitors versus dipeptidyl peptidase 4 inhibitors on cardiovascular function in patients with type 2 diabetes mellitus and coronary artery disease. J Obes Metab Syndr. 2019;28(4):254–261. doi: 10.7570/jomes.2019.28.4.254
  66. Lan NSR, Fegan PG, Yeap BB, Dwivedi G. The effects of sodium-glucose cotransporter 2 inhibitors on left ventricular function: current evidence and future directions. ESC Heart Fail. 2019;6(5):927–935. doi: 10.1002/ehf2.12505
  67. Hammoudi N, Jeong D, Singh R, et al. Empagliflozin improves left ventricular diastolic dysfunction in a genetic model of type 2 diabetes. Cardiovasc Drugs Ther. 2017;31(3):233–246. doi: 10.1007/s10557-017-6734-1
  68. De Marco VG, Aroor AR, Nistala R, et al. Sodium glucose transporter type 2 (SGLT2) inhibitor, empagliflozin, improves diastolic function in female diabetic db/db mice. Diabetes. 2015;64: A552.
  69. Joubert M, Jagu B, Montaigne D, et al. The sodium-glucose cotransporter 2 inhibitor dapagliflozin prevents cardiomyopathy in a diabetic lipodystrophic mouse model. Diabetes. 2017;66(4): 1030–1040. doi: 10.2337/db16-0733
  70. Pabel S, Wagner S, Bollenberg H, et al. Empagliflozin directly improves diastolic function in human heart failure. Eur J Heart Fail. 2018;20(12):1690–1700. doi: 10.1002/ejhf.1328
  71. Connelly KA, Zhang Y, Visram A, et al. Empagliflozin improves diastolic function in a nondiabetic rodent model of heart failure with preserved ejection fraction. JACC Basic Transl Sci. 2019;4(1):27–37. doi: 10.1016/j.jacbts.2018.11.010
  72. Connelly KA, Zhang Y, Desjardins J-F, et al. Load-independent effects of empagliflozin contribute to improve cardiac function in experimental heart failure with reduced ejection fraction. Cardiovasc Diabetol. 2020;19(1):13. doi: 10.1186/s12933-020-0994-y
  73. Zhang N, Feng B, Ma X, et al. Dapagliflozin improves left ventricular remodeling and aorta sympathetic tone in a pig model of heart failure with preserved ejection fraction. Cardiovasc Diabetol. 2019;18(1):107. doi: 10.1186/s12933-019-0914-1.

Copyright (c) 2021 Zverev Y.F., Rykunova A.Y.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77 - 65565 от 04.05.2016 г.


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies