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Evogliptin, a DPP-4 inhibitor, prevents diabetic cardiomyopathy by alleviating cardiac lipotoxicity in db/db mice

이주미|윤형록|Won Jong Chul|Pham Trong Kha|Nguyen To Hoai T.|Kim Gwang Sil|Kim Hyoung Kyu
생화학분자생물학회 (Korean Society Of Biochemistry And Molecular Biology)|2023.12|Experimental and Molecular Medicine|제55권 |pp. 767-779|DOI 10.1038/s12276-023-00958-6

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초록

Dipeptidyl peptidase-4 (DPP-4) inhibitors are glucose-lowering drugs for type 2 diabetes mellitus (T2DM). We investigated whether evogliptin® (EVO), a DPP-4 inhibitor, could protect against diabetic cardiomyopathy (DCM) and the underlying mechanisms. Eight-week-old diabetic and obese db/db mice were administered EVO (100 mg/kg/day) daily by oral gavage for 12 weeks. db/db control mice and C57BLKS/J as wild-type (WT) mice received equal amounts of the vehicle. In addition to the hypoglycemic effect, we examined the improvement in cardiac contraction/relaxation ability, cardiac fibrosis, and myocardial hypertrophy by EVO treatment. To identify the mechanisms underlying the improvement in diabetic cardiomyopathy by EVO treatment, its effect on lipotoxicity and the mitochondrial damage caused by lipid droplet accumulation in the myocardium were analyzed. EVO lowered the blood glucose and HbA1c levels and improved insulin sensitivity but did not affect the body weight or blood lipid profile. Cardiac systolic/diastolic function, hypertrophy, and fibrosis were improved in the EVO-treated group. EVO prevented cardiac lipotoxicity by reducing the accumulation of lipid droplets in the myocardium through suppression of CD36, ACSL1, FABP3, PPARgamma, and DGAT1 and enhancement of the phosphorylation of FOXO1, indicating its inhibition. The EVO-mediated improvement in mitochondrial function and reduction in damage were achieved through activation of PGC1a/NRF1/TFAM, which activates mitochondrial biogenesis. RNA-seq results for the whole heart confirmed that EVO treatment mainly affected the differentially expressed genes (DEGs) related to lipid metabolism. Collectively, these findings demonstrate that EVO improves cardiac function by reducing lipotoxicity and mitochondrial injury and provides a potential therapeutic option for DCM.

Abstract

Dipeptidyl peptidase-4 (DPP-4) inhibitors are glucose-lowering drugs for type 2 diabetes mellitus (T2DM). We investigated whether evogliptin® (EVO), a DPP-4 inhibitor, could protect against diabetic cardiomyopathy (DCM) and the underlying mechanisms. Eight-week-old diabetic and obese db/db mice were administered EVO (100 mg/kg/day) daily by oral gavage for 12 weeks. db/db control mice and C57BLKS/J as wild-type (WT) mice received equal amounts of the vehicle. In addition to the hypoglycemic effect, we examined the improvement in cardiac contraction/relaxation ability, cardiac fibrosis, and myocardial hypertrophy by EVO treatment. To identify the mechanisms underlying the improvement in diabetic cardiomyopathy by EVO treatment, its effect on lipotoxicity and the mitochondrial damage caused by lipid droplet accumulation in the myocardium were analyzed. EVO lowered the blood glucose and HbA1c levels and improved insulin sensitivity but did not affect the body weight or blood lipid profile. Cardiac systolic/diastolic function, hypertrophy, and fibrosis were improved in the EVO-treated group. EVO prevented cardiac lipotoxicity by reducing the accumulation of lipid droplets in the myocardium through suppression of CD36, ACSL1, FABP3, PPARgamma, and DGAT1 and enhancement of the phosphorylation of FOXO1, indicating its inhibition. The EVO-mediated improvement in mitochondrial function and reduction in damage were achieved through activation of PGC1a/NRF1/TFAM, which activates mitochondrial biogenesis. RNA-seq results for the whole heart confirmed that EVO treatment mainly affected the differentially expressed genes (DEGs) related to lipid metabolism. Collectively, these findings demonstrate that EVO improves cardiac function by reducing lipotoxicity and mitochondrial injury and provides a potential therapeutic option for DCM.

참고문헌 (58)

  1. Galicia-Garcia, U., "Pathophysiology of type 2 diabetes mellitus", Int. J. Mol. Sci, 21, pp.62~75 (2020)
  2. Saeedi, P., "Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045 : results from the International Diabetes Federation Diabetes Atlas, 9(th)", Diabetes Res. Clin. Pract, 157, pp.107843~ (2019)
  3. Dal Canto, E., "Diabetes as a cardiovascular risk factor : an overview of global trends of macro and micro vascular complications", Eur. J. Prev. Cardiol, 26, pp.25~32 (2019)
  4. Boudina, S., "Diabetic cardiomyopathy, causes and effects", Rev. Endocr. Metab. Disord, 11, pp.31~39 (2010)
  5. Paolillo, S., "Diabetic cardiomyopathy : definition, diagnosis, and therapeutic implications", Heart. Fail. Clin, 15, pp.341~347 (2019)
  6. Seferovic, P. M., "Type 2 diabetes mellitus and heart failure : a position statement from the Heart Failure Association of the European Society of Cardiology", Eur. J. Heart. Fail, 20, pp.853~872 (2018)
  7. Parim, B., "Diabetic cardiomyopathy : molecular mechanisms, detrimental effects of conventional treatment, and beneficial effects of natural therapy", Heart. Fail. Rev, 24, pp.279~299 (2019)
  8. Marwick, T. H., "Implications of underlying mechanisms for the recognition and management of diabetic cardiomyopathy", J. Am. Coll Cardiol, 71, pp.339~351 (2018)
  9. Jia, G., "Diabetic cardiomyopathy : an update of mechanisms contributing to this clinical entity", Circ. Res, 122, pp.624~638 (2018)
  10. Russo, I., "Diabetes-associated cardiac fibrosis : cellular effectors, molecular mechanisms and therapeutic opportunities", J. Mol. Cell. Cardiol, 90, pp.84~93 (2016)
  11. Goldberg, I. J., "Lipid metabolism and toxicity in the heart", Cell Metab, 15, pp.805~812 (2012)
  12. D’Souza, K., "Lipid metabolism and signaling in cardiac lipotoxicity", Biochim. Biophys. Acta, 1861, pp.1513~1524 (2016)
  13. Unger, R. H., "Lipoapoptosis : its mechanism and its diseases", Biochim. Biophys. Acta, 1585, pp.202~212 (2002)
  14. Mahajan, R., "Impact of obesity on cardiac metabolism, fibrosis, and function", Trends. Cardiovasc. Med, 25, pp.119~126 (2015)
  15. Elezaby, A., "Mitochondrial remodeling in mice with cardiomyocyte-specific lipid overload", J. Mol. Cell. Cardiol, 79, pp.275~283 (2015)
  16. Schrauwen, P., "Mitochondrial dysfunction and lipotoxicity", Biochim. Biophys. Acta, 1801, pp.266~271 (2010)
  17. Ussher, J. R, "Cardiovascular actions of incretin-based therapies", Circ. Res, 114, pp.1788~1803 (2014)
  18. Matsubara, J., "Dipeptidyl peptidase-4 inhibitor, sitagliptin, improves endothelial dysfunction in association with its anti-inflammatory effects in patients with coronary artery disease and uncontrolled diabetes", Circ. J, 77, pp.1337~1344 (2013)
  19. Aroor, A. R., "Dipeptidylpeptidase inhibition is associated with improvement in blood pressure and diastolic function in insulin-resistant male Zucker obese rats", Endocrinology, 154, pp.2501~2513 (2013)
  20. Kim, J. H., "Protective effects of evogliptin on steatohepatitis in high-fat-fed mice", Int. J. Mol. Sci, 21, pp.6743~ (2020)
  21. Nguyen, P. A., "Modulation of Sirt1", NF-kappaB interaction of evogliptin is attributed to inhibition of vascular inflammatory response leading to attenuation of atherosclerotic plaque formation, 2019, pp.168, 452~464
  22. 김미경, "Prevention and treatment effect of evogliptin on hepatic steatosis in high-fat-fed animal models", Archives of Pharmacal Research, 40(2), pp.268~281 (2017), 대한약학회
  23. Chae, Y. N., "Beneficial effects of evogliptin, a novel dipeptidyl peptidase 4inhibitor, on adiposity with increased Ppargc1a in white adipose tissue in obese mice", PLoS One, 10, pp.e0144064~ (2015)
  24. Kalayci, A., "Echocardiographic assessment of insulin-like growth factor binding protein-7 and early identification of acute heart failure", ESC Heart Fail, 7, pp.1664~1675 (2020)
  25. Ko, T., "Cardiac fibroblasts regulate the development of heart failure via Htra3-TGF-β-IGFBP7 axis", Nat. Commun, 13, pp.3275~ (2022)
  26. Gureev, A. P., "Regulation of mitochondrial biogenesis as a way for active longevity : interaction between the Nrf2 and PGC-1α signaling pathways", Front. Genet, 10, pp.435~ (2019)
  27. Nahlé, Z., "CD36-dependent regulation of muscle FoxO1 and PDK4 in the PPAR delta", beta-mediated adaptation to metabolic stress, 2008, pp.283, 14317~14326
  28. Verma, S. K., "Mitochondrial dysfunction and its impact on diabetic heart", Biochim. Biophys. Acta Mol. Basis Dis, 1863, pp.1098~1105 (2017)
  29. Goldfine, A. B., "Assessing the cardiovascular safety of diabetes therapies", N. Engl. J. Med, 359, pp.1092~1095 (2008)
  30. American Diabetes, A., "Pharmacologic approaches to glycemic treatment:standards of medical care in diabetes-2018", Diabetes Care, 41, pp.S73~S85 (2018)
  31. Nauck, M. A., "Cardiovascular actions and clinical outcomes with glucagon-like peptide-1receptor agonists and dipeptidyl peptidase-4 inhibitors", Circulation, 136, pp.849~870 (2017)
  32. Mulvihill, E. E, "Pharmacology, physiology, and mechanisms of action of dipeptidyl peptidase-4 inhibitors", Endocr. Rev, 35, pp.992~1019 (2014)
  33. Scheen, A. J., "Cardiovascular effects of gliptins", Nat. Rev. Cardiol, 10, pp.73~84 (2013)
  34. Lambeir, A. M., "Dipeptidyl-peptidase IV from bench to bedside : an update on structural properties, functions, and clinical aspects of the enzyme DPP IV", Crit. Rev. Clin. Lab. Sci, 40, pp.209~294 (2003)
  35. Zhong, J., "DPP4 in cardiometabolic disease : recent insights from the laboratory and clinical trials of DPP4 inhibition", Circ. Res, 116, pp.1491~1504 (2015)
  36. Scheen, A. J., "Cardiovascular effects of new oral glucose-lowering agents : DPP-4and SGLT-2 inhibitors", Circ. Res, 122, pp.1439~1459 (2018)
  37. Kim, T. H., "Hepatic role in an early glucose-lowering effect by a novel dipeptidyl peptidase 4 inhibitor, evogliptin, in a rodent model of type 2 diabetes", Eur. J. Pharmacol, 771, pp.65~76 (2016)
  38. Tan, X., "Evogliptin : a new dipeptidyl peptidase inhibitor for the treatment of type 2 diabetes", Expert Opin. Pharmacother, 17, pp.1285~1293 (2016)
  39. Jung, C. H., "A randomized, double-blind, placebo-controlled, phase II clinical trial to investigate the efficacy and safety of oral DA-1229 in patients with type 2diabetes mellitus who have inadequate glycaemic control with diet and exercise", Diabetes Metab. Res. Rev, 31, pp.295~306 (2015)
  40. Kim, T. H., "Additive effects of evogliptin in combination with pioglitazone on fasting glucose control through direct and indirect hepatic effects in diabetic mice", Eur. J. Pharmacol, 830, pp.95~104 (2018)
  41. Bernardo, B. C., "Molecular distinction between physiological and pathological cardiac hypertrophy : experimental findings and therapeutic strategies", Pharmacol. Ther, 128, pp.191~227 (2010)
  42. Yue, Y., "Transforming growth factor beta(TGF-beta)mediates cardiac fibrosis and induces diabetic cardiomyopathy", Diabetes Res. Clin. Pract, 133, pp.124~130 (2017)
  43. Barroso, M. C., "Serum insulin-like growth factor-1 and its binding protein-7 : potential novel biomarkers for heart failure with preserved ejection fraction", BMC Cardiovasc. Disord, 16, pp.199~ (2016)
  44. He, F., "NRF2, a Transcription Factor for Stress Response and Beyond", Int. J. Mol. Sci, 21, pp.4777~ (2020)
  45. Ohtsuji, M., "Nrf1 and Nrf2 play distinct roles in activation of antioxidant response element-dependent genes", J. Biol. Chem, 283, pp.33554~33562 (2008)
  46. Lenski, M., "Effects of DPP-4 inhibition on cardiac metabolism and function in mice", J. Mol. Cell. Cardiol, 51, pp.906~918 (2011)
  47. Rowe, G. C., "PGC-1 coactivators in cardiac development and disease", Circ. Res, 107, pp.825~838 (2010)
  48. Alvarez-Guardia, D., "The p65 subunit of NF-kappaB binds to PGC-1alpha, linking inflammation and metabolic disturbances in cardiac cells", Cardiovasc. Res, 87, pp.449~458 (2010)
  49. Choi, B., "Evogliptin suppresses calcific aortic valve disease by attenuating inflammation, fibrosis, and calcification", Cells, 10, pp.57~ (2021)
  50. Buchanan, J., "Reduced cardiac efficiency and altered substrate metabolism precedes the onset of hyperglycemia and contractile dysfunction in two mouse models of insulin resistance and obesity", Endocrinology, 146, pp.5341~5349 (2005)
  51. Mazumder, P. K., "Impaired cardiac efficiency and increased fatty acid oxidation in insulin-resistant ob", ob mouse hearts, 2004, pp.53, 2366~2374
  52. Chabowski, A., "Protein-mediated fatty acid uptake in the heart", Curr. Cardiol. Rev, 4, pp.12~21 (2008)
  53. Zhang, Y., "Cardiospecific CD36 suppression by lentivirus-mediated RNA interference prevents cardiac hypertrophy and systolic dysfunction in high-fatdiet induced obese mice", Cardiovasc. Diabetol, 14, pp.69~ (2015)
  54. Zhuang, L., "FABP3 deficiency exacerbates metabolic derangement in cardiac hypertrophy and heart failure via PPARalpha pathway", Front. Cardiovasc. Med, 8, pp.722908~ (2021)
  55. Kvandová, M., "The role of PPARgamma in cardiovascular diseases", Physiol. Res, 65, pp.S343~s363 (2016)
  56. Finck, B. N., "The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus", J. Clin. Invest, 109, pp.121~130 (2002)
  57. Liu, F., "Upregulation of MG53 induces diabetic cardiomyopathy through transcriptional activation of peroxisome proliferation-activated receptor α", Circulation, 131, pp.795~804 (2015)
  58. Kyriazis, I. D., "KLF5 is induced by FOXO1 and causes oxidative stress and diabetic cardiomyopathy", Circ. Res, 128, pp.335~357 (2021)

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