Abstract
Diabetic cardiomyopathy (DCM) is a leading cause of death in diabetic patients, which is currently without available specific treatment. This study aimed to investigate the potential protective effects of pioglitazone (Pio) and curcumin (Cur) against DCM in type 1 diabetes mellitus (T1DM), with pointing to their role on Ca+2/calmodulin-dependent protein kinase II (CaMKII) and peroxisome proliferator–activated receptor gamma (PPAR-γ) expression. Diabetes was induced in adult male Sprague Dawley rats by administration of single intraperitoneal injection of streptozotocin (STZ) (52.5 mg/kg). Diabetic rats were administered either Pio (20 mg/kg/day) or Cur (100 mg/kg/day) orally for 6 weeks. Treatment with Pio and/or Cur markedly reduced serum cardiac injury markers and lipid profile markers in diabetic animals. Additionally, Pio and/or Cur treatment mitigated oxidative stress and fibrosis in diabetic rats as evident from the significant suppression in myocardial lipid peroxidation and tumor growth factor beta 1 (TGF-β1) level, with concomitant significant elevation in total antioxidant capacity (TAC) and improvement in histopathological architecture of heart tissue. Pio/Cur treatment protocol accomplished its cardioprotective effect by depressing cardiac CaMKII/NF-κB signaling accompanied by enhancement in PPAR-γ expression. Conclusively, these findings demonstrated the therapeutic potential of Pio/Cur regimen in alleviating DCM in T1DM through modulation of CaMKII and PPAR-γ expression.
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Abdelsamia EM, Khaleel SA, Balah A, Baky NAA (2019) Curcumin augments the cardioprotective effect of metformin in an experimental model of type I diabetes mellitus; impact of Nrf2/HO-1 and JAK/STAT pathways. Biomed Pharmacother 109:2136–2144. https://doi.org/10.1016/j.biopha.2018.11.064
Ahmadian M, Suh JM, Hah N, Liddle C, Atkins AR, Downes M, Evans RM (2013) PPARγ signaling and metabolism: the good, the bad and the future. Nat Med 19(5):557–566. https://doi.org/10.1038/nm.3159
Ali RM, Al-Shorbagy MY, Helmy MW, El-Abhar HS (2018) Role of Wnt4/β-catenin, Ang II/TGFβ, ACE2, NF-κB, and IL-18 in attenuating renal ischemia/reperfusion-induced injury in rats treated with vit D and pioglitazone. Eur J Pharmacol 831:68–76. https://doi.org/10.1016/j.ejphar.2018.04.032
Banchroft JD, Stevens A, Turner D (1996) Theory and practice of histological techniques, 4th edn. Churchill Livingstone, New York
Beckendorf J, van den Hoogenhof MM, Backs J (2018) Physiological and unappreciated roles of CaMKII in the heart. Basic Res Cardiol 113(4):29. https://doi.org/10.1007/s00395-018-0688-8
Bhat R, Bhansali A, Bhadada S, Sialy R (2007) Effect of pioglitazone therapy in lean type1 diabetes mellitus. Diabetes Res Clin Pract 78(3):349–354. https://doi.org/10.1016/j.diabres.2007.04.012
Boudina S, Abel ED (2010) Diabetic cardiomyopathy, causes and effects. Rev Endocr Metab Disord 11(1):31–39. https://doi.org/10.1007/s11154-010-9131-7
Burgess HA, Daugherty LE, Thatcher TH, Lakatos HF, Ray DM, Redonnet M, Sime PJ (2005) PPARγ agonists inhibit TGF-β induced pulmonary myofibroblast differentiation and collagen production: implications for therapy of lung fibrosis. Am J Physiol Lung Cell Mol Physiol 288(6):L1146–L1153. https://doi.org/10.1152/ajplung.00383.2004
Chawla A, Boisvert WA, Lee CH, Laffitte BA, Barak Y, Joseph SB, Evans RM (2001) A PPARγ-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell 7(1):161–171. https://doi.org/10.1016/s1097-2765(01)00164-2
Chen XQ, Liu X, Wang QX, Zhang MJ, Guo M, Liu F, Zhou L (2015) Pioglitazone inhibits angiotensin II-induced atrial fibroblasts proliferation via NF-κB/TGF-β1/TRIF/TRAF6 pathway. Exp Cell Res 330(1):43–55. https://doi.org/10.1016/j.yexcr.2014.08.021
Collino M, Aragno M, Castiglia S, Miglio G, Tomasinelli C, Boccuzzi G, Fantozzi R (2010) Pioglitazone improves lipid and insulin levels in overweight rats on a high cholesterol and fructose diet by decreasing hepatic inflammation. Br J Pharmacol 160(8):1892–1902. https://doi.org/10.1111/j.1476-5381.2010.00671.x
DeGeeter M, Williamson B (2014) Alternative agents in type 1 diabetes in addition to insulin therapy: metformin, alpha-glucosidase inhibitors, pioglitazone, GLP-1 agonists, DPP-IV inhibitors, and SGLT-2 inhibitors. J Pharm Pract 29(2):144–159. https://doi.org/10.1177/0897190014549837
Di BB, Li HW, Li WP, Shen XH, Sun ZJ, Wu X (2014) Pioglitazone inhibits high glucose-induced expression of receptor for advanced glycation end products in coronary artery smooth muscle cells. Mol Med Rep 11(4):2601–2607. https://doi.org/10.3892/mmr.2014.3113
Elshazly S, Soliman E (2019) PPAR gamma agonist, pioglitazone, rescues liver damage induced by renal ischemia/reperfusion injury. Toxicol Appl Pharmacol 362:86–94. https://doi.org/10.1016/j.taap.2018.10.022
Erickson JR, He BJ, Grumbach IM, Anderson ME (2011) CaMKII in the cardiovascular system: sensing redox states. Physiol Rev 91(3):889–915. https://doi.org/10.1152/physrev.00018.2010
Fang ZY, Prins JB, Marwick TH (2004) Diabetic cardiomyopathy: evidence, mechanisms, and therapeutic implications. Endocr Rev 25(4):543–567. https://doi.org/10.1210/er.2003-0012
Fazel Nabavi S, Thiagarajan R, Rastrelli L, Daglia M, Sobarzo-Sanchez E, Alinezhad H, Mohammad Nabavi S (2015) Curcumin: a natural product for diabetes and its complications. Curr Top Med Chem 15(23):2445–2455. https://doi.org/10.2174/1568026615666150619142519
Guo S, Meng XW, Yang XS, Liu XF, Ou-Yang CH, Liu C (2017) Curcumin administration suppresses collagen synthesis in the hearts of rats with experimental diabetes. Acta Pharmacol Sin 39(2):195–204. https://doi.org/10.1038/aps.2017.92
Haidara MA, Yassin HZ, Rateb M, Ammar H, Zorkani MA (2006) Role of oxidative stress in development of cardiovascular complications in diabetes mellitus. Curr Vasc Pharmacol 4(3):215–227. https://doi.org/10.2174/157016106777698469
Hara T, Mahadevan J, Kanekura K, Hara M, Lu S, Urano F (2014) Calcium efflux from the endoplasmic reticulum leads to β-cell death. Endocrinology. 155(3):758–768. https://doi.org/10.1210/en.2013-1519
Hegyi B, Bers DM, Bossuyt J (2019) CaMKII signaling in heart diseases: emerging role in diabetic cardiomyopathy. J Mol Cell Cardiol 127:246–259. https://doi.org/10.1016/j.yjmcc.2019.01.001
Hobson MJ, Hake PW, O’Connor M, Schulte C, Moore V, James JM, Zingarelli B (2014) Conditional deletion of cardiomyocyte peroxisome proliferator-activated receptor-γ enhances myocardial ischemia-reperfusion injury in mice. Shock. 41(1):40–47. https://doi.org/10.1097/SHK.0000000000000051
Ibrahim MA, El-Sheikh AA, Khalaf HM, Abdelrahman AM (2014) Protective effect of peroxisome proliferator activator receptor (PPAR)-α and-γ ligands against methotrexate-induced nephrotoxicity. Immunopharmacol Immunotoxicol 36(2):130–137. https://doi.org/10.3109/08923973.2014.884135
Javeri I, Chand N (2016) Curcumin. In: Nutraceuticals. Academic Press, pp 435–445
Jia G, Hill MA, Sowers JR (2018) Diabetic cardiomyopathy: an update of mechanisms contributing to this clinical entity. Circ Res 122(4):624–638. https://doi.org/10.1161/CIRCRESAHA.117.311586
Kistamás K, Szentandrássy N, Hegyi B, Ruzsnavszky F, Váczi K, Bárándi L, Kecskeméti V (2013) Effects of pioglitazone on cardiac ion currents and action potential morphology in canine ventricular myocytes. Eur J Pharmacol 710(1–3):10–19. https://doi.org/10.1016/j.ejphar.2013.03.047
Kocaadam B, Şanlier N (2017) Curcumin, an active component of turmeric (Curcuma longa), and its effects on health. Crit Rev Food Sci Nutr 57(13):2889–2895. https://doi.org/10.1080/10408398.2015.1077195
Kumar D, Singla SK, Puri V, Puri S (2015) The restrained expression of NF-kB in renal tissue ameliorates folic acid induced acute kidney injury in mice. PLoS One 10(1):e115947. https://doi.org/10.1371/journal.pone.0115947
Kurtz M, Capobianco E, Martinez N, Roberti SL, Arany E, Jawerbaum A (2014) PPAR ligands improve impaired metabolic pathways in fetal hearts of diabetic rats. J Mol Endocrinol 53(2):237–246. https://doi.org/10.1530/JME-14-0063
Lan YANG, Zhou Q, Wu ZL (2004) NF-kappa B involved in transcription enhancement of TGF-beta 1 induced by Ox-LDL in rat mesangial cells. Chin Med J 117(2):225–230
Lee TI, Kao YH, Chen YC, Huang JH, Hsiao FC, Chen YJ (2013) Peroxisome proliferator-activated receptors modulate cardiac dysfunction in diabetic cardiomyopathy. Diabetes Res Clin Pract 100(3):330–339. https://doi.org/10.1016/j.diabres.2013.01.008
Li Q, Engelhardt JF (2006) Interleukin-1β induction of NFκB is partially regulated by H2O2-mediated activation of NFκB-inducing kinase. J Biol Chem 281(3):1495–1505. https://doi.org/10.1074/jbc.M511153200
Li J, Wang P, Ying J, Chen Z, Yu S (2016) Curcumin attenuates retinal vascular leakage by inhibiting calcium/calmodulin-dependent protein kinase II activity in streptozotocin-induced diabetes. Cell Physiol Biochem 39(3):1196–1208. https://doi.org/10.1159/000447826
Liang E, Liu X, Du Z, Yang R, Zhao Y (2018) Andrographolide ameliorates diabetic cardiomyopathy in mice by blockage of oxidative damage and NF-κB-mediated inflammation. Oxidative Med Cell Longev 9086747(13):1–13. https://doi.org/10.1155/2018/9086747
Lingappan K (2018) NF-κB in oxidative stress. Curr Opin Toxicol 7:81–86. https://doi.org/10.1016/j.cotox.2017.11.002
Liu RM, Pravia KG (2010) Oxidative stress and glutathione in TGF-β-mediated fibrogenesis. Free Radic Biol Med 48(1):1–15. https://doi.org/10.1016/j.freeradbiomed.2009.09.026
Liu HJ, Liao HH, Yang Z, Tang QZ (2016) Peroxisome proliferator-activated receptor-γ is critical to cardiac fibrosis. PPAR Res 2016. https://doi.org/10.1155/2016/2198645
Luo M, Guan X, Luczak ED, Lang D, Kutschke W, Gao Z, Weiss RM (2013) Diabetes increases mortality after myocardial infarction by oxidizing CaMKII. J Clin Invest 123(3):1262–1274. https://doi.org/10.1172/JCI65268
Martin TP, Lawan A, Robinson E, Grieve DJ, Plevin R, Paul A, Currie S (2013) Adult cardiac fibroblast proliferation is modulated by calcium/calmodulin-dependent protein kinase II in normal and hypertrophied hearts. Pflugers Arch 466(2):319–330. https://doi.org/10.1007/s00424-013-1326-9
Meng XM, Nikolic-Paterson DJ, Lan HY (2016) TGF-β: the master regulator of fibrosis. Nat Rev Nephrol 12(6):325–338. https://doi.org/10.1038/nrneph.2016.48
Miyazaki Y, Matsuda M, DeFronzo RA (2002) Dose-response effect of pioglitazone on insulin sensitivity and insulin secretion in type 2 diabetes. Diabetes Care 25(3):517–523. https://doi.org/10.2337/diacare.25.3.517
Ni T, Lin N, Lu W, Sun Z, Lin H, Chi J, Guo H (2020) Dihydromyricetin prevents diabetic cardiomyopathy via miR-34a suppression by activating autophagy. Cardiovasc Drugs Ther 34:1–11. https://doi.org/10.1007/s10557-020-06968-0
Omura T, Yoshiyama M, Kim S, Matsumoto R, Nakamura Y, Izumi Y, Takeuchi K (2004) Involvement of apoptosis signal-regulating kinase-1 on angiotensin II-induced monocyte chemoattractant protein-1 expression. J Cardiovasc Pharmacol 24(2):270–275. https://doi.org/10.1161/01.ATV.0000112930.40564.89
Ruiz S, Pergola PE, Zager RA, Vaziri ND (2013) Targeting the transcription factor Nrf2 to ameliorate oxidative stress and inflammation in chronic kidney disease. Kidney Int 83(6):1029–1041. https://doi.org/10.1038/ki.2012.439
Rusciano MR, Sommariva E, Douin-Echinard V, Ciccarelli M, Poggio P, Maione AS (2019) CaMKII activity in the inflammatory response of cardiac diseases. Int J Mol Sci 20(18):4374. https://doi.org/10.3390/ijms20184374
Russo I, Frangogiannis NG (2015) Diabetes-associated cardiac fibrosis: cellular effectors, molecular mechanisms and therapeutic opportunities. J Mol Cell Cardiol 90:84–93. https://doi.org/10.1016/j.yjmcc.2015.12.011
Salem KA, Sydorenko V, Qureshi M, Oz M, Howarth FC (2018) Effects of pioglitazone on ventricular myocyte shortening and Ca 2+ transport in the Goto-Kakizaki type 2 diabetic rat. Physiol Res 67(1):10.33549/physiolres.933567
Seferović PM, Paulus WJ (2015) Clinical diabetic cardiomyopathy: a two-faced disease with restrictive and dilated phenotypes. Eur Heart J 36(27):1718–1727. https://doi.org/10.1093/eurheartj/ehv134
Shida T, Nozawa T, Sobajima M, Ihori H, Matsuki A, Inoue H (2014) Fluvastatin-induced reduction of oxidative stress ameliorates diabetic cardiomyopathy in association with improving coronary microvasculature. Heart Vessel 29(4):532–541. https://doi.org/10.1007/s00380-013-0402-6
Singh MV, Kapoun A, Higgins L, Kutschke W, Thurman JM, Zhang R, Weiss RM (2009) Ca 2+/calmodulin-dependent kinase II triggers cell membrane injury by inducing complement factor B gene expression in the mouse heart. J Clin Invest 119(4):986–996. https://doi.org/10.1172/JCI35814
Soetikno V, Sari FR, Sukumaran V, Lakshmanan AP, Mito S, Harima M, Watanabe K (2012) Curcumin prevents diabetic cardiomyopathy in streptozotocin-induced diabetic rats: possible involvement of PKC–MAPK signaling pathway. Eur J Pharm Sci 47(3):604–614. https://doi.org/10.1016/j.ejps.2012.04.018
Soliman E, Behairy SF, El-maraghy NN, Elshazly SM (2019) PPAR-γ agonist, pioglitazone, reduced oxidative and endoplasmic reticulum stress associated with L-NAME-induced hypertension in rats. Life Sci 239:117047. https://doi.org/10.1016/j.lfs.2019.117047
Suetomi T, Willeford A, Brand CS, Cho Y, Ross RS, Miyamoto S, Brown JH (2018) Inflammation and NLRP3 inflammasome activation initiated in response to pressure overload by Ca2+/Calmodulin-dependent protein kinase II δ signaling in cardiomyocytes are essential for adverse cardiac remodeling. Circulation. 138(22):2530–2544. https://doi.org/10.1161/CIRCULATIONAHA.118.034621
Tesch GH, Allen TJ (2007) Rodent models of streptozotocin-induced diabetic nephropathy (methods in renal research). Nephrology (Carlton) 12(3):261–266. https://doi.org/10.1111/j.1440-1797.2007.00796.x
Wassef MAE, Tork OM, Rashed LA, Ibrahim W, Morsi H, Rabie DMM (2018) Mitochondrial dysfunction in diabetic cardiomyopathy: effect of mesenchymal stem cell with ppar-γ agonist or exendin-4. Exp Clin Endocrinol Diabetes 126(01):27–38. https://doi.org/10.1055/s-0043-106859
Wei J, Bhattacharyya S, Varga J (2010) Peroxisome proliferator-activated receptor γ: innate protection from excessive fibrogenesis and potential therapeutic target in systemic sclerosis. Curr Opin Rheumatol 22(6):671–676. https://doi.org/10.1097/BOR.0b013e32833de1a7
Xie Z, Wu B, Shen G, Li X, Wu Q (2018) Curcumin alleviates liver oxidative stress in type 1 diabetic rats. Mol Med Rep 17(1):103–108. https://doi.org/10.3892/mmr.2017.7911
Yao Q, Ke ZQ, Guo S, Yang XS, Zhang FX, Liu XF, Liu C (2018) Curcumin protects against diabetic cardiomyopathy by promoting autophagy and alleviating apoptosis. J Mol Cell Cardiol 124:26–34. https://doi.org/10.1016/j.yjmcc.2018.10.004
Yu W, Wu J, Cai F, Xiang J, Zha W, Fan D, Liu C (2012) Curcumin alleviates diabetic cardiomyopathy in experimental diabetic rats. PLoS One 7(12):e52013. https://doi.org/10.1371/journal.pone.0052013
Yuan M, Qiu M, Cui J, Zhang X, Zhang P (2014) Protective effects of pioglitazone against immunoglobulin deposition on heart of streptozotocin-induced diabetic rats. J Endocrinol Investig 37(4):375–384. https://doi.org/10.1007/s40618-013-0046-5
Yue Y, Meng K, Pu Y, Zhang X (2017) Transforming growth factor beta (TGF-β) mediates cardiac fibrosis and induces diabetic cardiomyopathy. Diabetes Res Clin Pract 133:124–130. https://doi.org/10.1016/j.diabres.2017.08.018
Zhang W, Chen DQ, Qi F, Wang J, Xiao WY, Zhu WZ (2010) Inhibition of calcium–calmodulin-dependent kinase II suppresses cardiac fibroblast proliferation and extracellular matrix secretion. J Cardiovasc Pharmacol 55(1):96–105. https://doi.org/10.1097/FJC.0b013e3181c9548b
Zhang B, Zhai M, Li B, Liu Z, Li K, Jiang L, Liang H (2018, 2018) Honokiol ameliorates myocardial ischemia/reperfusion injury in type 1 diabetic rats by reducing oxidative stress and apoptosis through activating the SIRT1-Nrf2 signaling pathway. Oxidative Med Cell Longev. https://doi.org/10.1155/2018/3159801
Zhong CB, Chen X, Zhou XY, Wang XB (2018) The role of peroxisome proliferator-activated receptor γ in mediating cardioprotection against ischemia/reperfusion injury. J Cardiovasc Pharmacol Ther 23(1):46–56. https://doi.org/10.1177/1074248417707049
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AG: Performed the experiments, collected the data, analyzed the data, and performed the graphical and statistical analysis; NA: Developed the research idea, designed the experiments, supervised the experiment execution, supervised the data analysis, and wrote and revised the manuscript; EM and HZ: Supervised the experiment execution, supervised the data analysis, and revised the manuscript. All authors read and approved the manuscript, and all data were generated in-house and that no paper mill was used.
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Gbr, A.A., Abdel Baky, N.A., Mohamed, E.A. et al. Cardioprotective effect of pioglitazone and curcumin against diabetic cardiomyopathy in type 1 diabetes mellitus: impact on CaMKII/NF-κB/TGF-β1 and PPAR-γ signaling pathway. Naunyn-Schmiedeberg's Arch Pharmacol 394, 349–360 (2021). https://doi.org/10.1007/s00210-020-01979-y
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DOI: https://doi.org/10.1007/s00210-020-01979-y