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Cardioprotective effects of rutin via alteration in TNF-α, CRP, and BNP levels coupled with antioxidant effect in STZ-induced diabetic rats

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Abstract

Diabetic cardiomyopathy (DCM) is a dreadful complication of diabetes responsible for 80 % mortality in diabetic patients, but unfortunately its pharmacotherapy is still incomplete. Rutin is a naturally occurring flavonoid having a long history of use in nutritional supplements for its action against oxidative stress, inflammation, and hyperglycemia, the key players involved in the progression of DCM, but remains unexplored for its role in DCM. This study was conducted to address this lacuna. It was performed in 4-week-old Streptozotocin-induced (45 mg/kg) diabetic rats for a period of 24 weeks to mimic the cardiotoxic effect of chronic hyperglycemia in diabetic patient’s heart and to investigate the effect of rutin (50 mg/kg/day) in ameliorating these effects. Heart of the diabetic rats showed altered ECG parameters, reduced total antioxidant capacity, increased inflammatory assault, and degenerative changes. Interestingly, rutin treatment significantly ameliorated these changes with decrease in blood glucose level (p > 0.001), % HbA1c (p > 0.001) and reduced expression of TNF-α (p < 0.001), CRP (p < 0.001), and BNP (p < 0.01) compared to diabetic control rats. In addition, rutin provided significant protection against diabetes associated oxidative stress (p < 0.05), prevented degenerative changes in heart, and improved ECG parameters compared to diabetic control rats. The heart-to-body weight ratio was significantly reduced in rutin treatment group compared to diabetic control rats (p < 0.001). In conclusion, this study implicates that oxidative stress and inflammation are the central players involved in the progression of DCM and rutin ameliorates DCM through its antioxidant and anti-inflammatory actions on heart.

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References

  1. van Dieren DS, Beulens JW, van der Schouw YT, Grobbee DE, Neal B (2010) The global burden of diabetes and its complications: an emerging pandemic. Eur J Cardiovasc Prev Rehabil 17(Suppl 1):S3–S8. doi:10.1097/01.hjr.0000368191.86614.5a

    Article  PubMed  Google Scholar 

  2. Boudina S, Abel ED (2010) Diabetic cardiomyopathy, causes and effects. Rev Endocr Metab Disord 11:31–39. doi:10.1007/s11154-010-9131-7

    Article  PubMed  PubMed Central  Google Scholar 

  3. Huynh K, Bernardo BC, McMullen JR, Ritchie RH (2014) Diabetic cardiomyopathy: mechanisms and new treatment strategies targeting antioxidant signaling pathways. Pharmacol Ther 142:375–415. doi:10.1016/j.pharmthera.2014.01.003

    Article  CAS  PubMed  Google Scholar 

  4. Cai L, Kang YJ (2001) Oxidative stress and diabetic cardiomyopathy: a brief review. Cardiovasc Toxicol 1:181–193. doi:10.1385/CT:1:3:181

    Article  CAS  PubMed  Google Scholar 

  5. Giacco F, Brownlee M (2010) Oxidative stress and diabetic complications. Circ Res 107:1058–1070. doi:10.1161/CIRCRESAHA.110.223545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Remmen HV, Williams MD, Guo Z et al (2001) Knockout mice heterozygous for Sod2 show alterations in cardiac mitochondrial function and apoptosis. Am J Physiol Heart Circ Physiol 281:H1422–H1432

    PubMed  Google Scholar 

  7. Pankuweit S, Ruppert V, Maisch B (2004) Inflammation in dilated cardiomyopathy. Herz 29:788–793. doi:10.1007/s00059-004-2626-9

    Article  PubMed  Google Scholar 

  8. Silva D, Pais de Lacerda A (2012) High-sensitivity C-reactive protein as a biomarker of risk in coronary artery disease. Rev Port Cardiol 31:733–745. doi:10.1016/j.repce.2012.09.006

    PubMed  Google Scholar 

  9. Wu C-K, Lee J-K, Chiang F-T et al (2011) Plasma levels of tumor necrosis factor-α and interleukin-6 are associated with diastolic heart failure through downregulation of sarcoplasmic reticulum Ca2+ ATPase. Crit Care Med 39:984–992. doi:10.1097/CCM.0b013e31820a91b9

    Article  CAS  PubMed  Google Scholar 

  10. Janczewski AM, Kadokami T, Lemster B et al (2003) Morphological and functional changes in cardiac myocytes isolated from mice overexpressing TNF-α. Am J Physiol Heart Circ Physiol 284:H960–H969. doi:10.1152/ajpheart.0718.2001

    Article  CAS  PubMed  Google Scholar 

  11. Rouet-Benzineb P, Buhler JM, Dreyfus P et al (1999) Altered balance between matrix gelatinases (MMP-2 and MMP-9) and their tissue inhibitors in human dilated cardiomyopathy: potential role of MMP-9 in myosin-heavy chain degradation. Eur J Heart Fail 1:337–352. doi:10.1016/S1388-9842(99)00048-3

    Article  CAS  PubMed  Google Scholar 

  12. Chua LS (2013) A review on plant-based rutin extraction methods and its pharmacological activities. J Ethnopharmacol 150:805–817. doi:10.1016/j.jep.2013.10.036

    Article  CAS  PubMed  Google Scholar 

  13. Kamalakkannan N, Prince PSM (2006) Antihyperglycaemic and antioxidant effect of rutin, a polyphenolic flavonoid, in streptozotocin-induced diabetic wistar rats. Basic Clin Pharmacol Toxicol 98:97–103. doi:10.1111/j.1742-7843.2006.pto_241.x

    Article  CAS  PubMed  Google Scholar 

  14. Hao G, Dong Y, Huo R, Wen K, Zhang Y, Liang G (2016) Rutin inhibits neuroinflammation and provides neuroprotection in an experimental rat model of subarachnoid hemorrhage, possibly through suppressing the Rage-NF-kappaB inflammatory signaling pathway. Neurochem Res 41:1496–1504. doi:10.1007/s11064-016-1863-7

    Article  CAS  PubMed  Google Scholar 

  15. Wu WB, Hung DK, Chang FW, Ong ET, Chen BH (2012) Anti-inflammatory and anti-angiogenic effects of flavonoids isolated from Lycium barbarum Linnaeus on human umbilical vein endothelial cells. Food Funct 3:1068–1081. doi:10.1039/C2FO30051F

    Article  CAS  PubMed  Google Scholar 

  16. Gupta SK, Dongare S, Mathur R et al (2015) Genistein ameliorates cardiac inflammation and oxidative stress in streptozotocin-induced diabetic cardiomyopathy in rats. Mol Cell Biochem 408:63–72. doi:10.1007/s11010-015-2483-2

    Article  CAS  PubMed  Google Scholar 

  17. Gupta SK, Kumar B, Nag TC et al (2011) Curcumin prevents experimental diabetic retinopathy in rats through its hypoglycemic, antioxidant, and anti-inflammatory mechanisms. J Ocul Pharmacol Ther 27:123–130. doi:10.1089/jop.2010.0123

    Article  CAS  PubMed  Google Scholar 

  18. Kumar B, Gupta SK, Nag TC et al (2014) Retinal neuroprotective effects of quercetin in streptozotocin-induced diabetic rats. Exp Eye Res 125:193–202. doi:10.1016/j.exer.2014.06.009

    Article  CAS  PubMed  Google Scholar 

  19. Kumar B, Gupta SK, Srinivasan BP et al (2012) Hesperetin ameliorates hyperglycemia induced retinal vasculopathy via anti-angiogenic effects in experimental diabetic rats. Vascul Pharmacol 57:201–207. doi:10.1016/j.vph.2012.02.007

    Article  CAS  PubMed  Google Scholar 

  20. Kumar B, Gupta SK, Srinivasan BP et al (2013) Hesperetin rescues retinal oxidative stress, neuroinflammation and apoptosis in diabetic rats. Microvasc Res 87:65–74. doi:10.1016/j.mvr.2013.01.002

    Article  CAS  PubMed  Google Scholar 

  21. Kannan MM, Quine SD (2011) Ellagic acid ameliorates isoproterenol induced oxidative stress: evidence from electrocardiological, biochemical and histological study. Eur J Pharmacol 659:45–52. doi:10.1016/j.ejphar.2011.02.037

    Article  CAS  PubMed  Google Scholar 

  22. Umbarkar P, Singh S, Arkat S et al (2015) Monoamine oxidase-A is an important source of oxidative stress and promotes cardiac dysfunction, apoptosis, and fibrosis in diabetic cardiomyopathy. Free Radic Biol Med 87:263–273. doi:10.1016/j.freeradbiomed.2015.06.025

    Article  CAS  PubMed  Google Scholar 

  23. Guo Z, Qin Z, Zhang R et al (2012) Effect of rosiglitazone on the expression of cardiac adiponectin receptors and NADPH oxidase in type 2 diabetic rats. Eur J Pharmacol 685:116–125. doi:10.1016/j.ejphar.2012.04.010

    Article  CAS  PubMed  Google Scholar 

  24. Hamblin M, Friedman DB, Hill S et al (2007) Alterations in the diabetic myocardial proteome coupled with increased myocardial oxidative stress underlies diabetic cardiomyopathy. J Mol Cell Cardiol 42:884–895. doi:10.1016/j.yjmcc.2006.12.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Felicio JS, Koury CC, Carvalho CT et al (2015) Present insights on cardiomyopathy in diabetic patients. Curr Diabetes Rev 12:1–12. doi:10.2174/1573399812666150914120529

    Article  Google Scholar 

  26. Asbun J, Villarreal FJ (2006) The pathogenesis of myocardial fibrosis in the setting of diabetic cardiomyopathy. J Am Coll Cardiol 47:693–700. doi:10.1016/j.jacc.2005.09.050

    Article  CAS  PubMed  Google Scholar 

  27. Epshteyn V, Morrison K, Krishnaswamy P et al (2003) Utility of B-type natriuretic peptide (BNP) as a screen for left ventricular dysfunction in patients With diabetes. Diabetes Care 26:2081–2087. doi:10.2337/diacare.26.7.2081

    Article  CAS  PubMed  Google Scholar 

  28. Li CJ, Lv L, Li H, Yu DM (2012) Cardiac fibrosis and dysfunction in experimental diabetic cardiomyopathy are ameliorated by alpha-lipoic acid. Cardiovasc Diabetol 11:73. doi:10.1186/1475-2840-11-73

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Mano Y, Anzai T, Kaneko H et al (2011) Overexpression of human C-reactive protein exacerbates left ventricular remodeling in diabetic cardiomyopathy. Circ J 75:1717–1727. doi:10.1253/circj.CJ-10-1199

    Article  CAS  PubMed  Google Scholar 

  30. Mohamad HE, Askar ME, Hafez MM (2011) Management of cardiac fibrosis in diabetic rats; the role of peroxisome proliferator activated receptor gamma (PPAR-gamma) and calcium channel blockers (CCBs). Diabetol Metab Syndr 3:4. doi:10.1186/1758-5996-3-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Arjumand W, Seth A, Sultana S (2011) Rutin attenuates cisplatin induced renal inflammation and apoptosis by reducing NFκB, TNF-α and caspase-3 expression in wistar rats. Food Chem Toxicol 49:2013–2021. doi:10.1016/j.fct.2011.05.012

    Article  CAS  PubMed  Google Scholar 

  32. Backes JM, Howard PA, Moriarty PM (2004) Role of C-reactive protein in cardiovascular disease. Ann Pharmacother 38:110–118. doi:10.1345/aph.1D203

    Article  CAS  PubMed  Google Scholar 

  33. Ilkhanizadeh B, Shirpoor A, Khadem Ansari MH, Nemati S, Rasmi Y (2016) Protective effects of ginger (Zingiber officinale) extract against diabetes-induced heart abnormality in rats. Diabetes Metab J 40:46–53. doi:10.4093/dmj.2016.40.1.46

    Article  PubMed  PubMed Central  Google Scholar 

  34. Dickstein K (2005) C-reactive protein in ischaemic cardiomyopathy: assessing vascular risk in heart failure. Eur Heart J 26:2218–2219. doi:10.1093/eurheartj/ehi464

    Article  PubMed  Google Scholar 

  35. Ronnow BS, Reyna SP, Muhlestein JB et al (2005) C-reactive protein predicts death in patients with non-ischemic cardiomyopathy. Cardiology 104:196–201. doi:10.1159/000088138

    Article  CAS  PubMed  Google Scholar 

  36. Whitsel EA, Boyko EJ, Rautaharju PM et al (2005) Electrocardiographic QT interval prolongation and risk of primary cardiac arrest in diabetic patients. Diabetes Care 28:2045–2047. doi:10.2337/diacare.28.8.2045

    Article  PubMed  Google Scholar 

  37. Veglio M, Giunti S, Stevens LK et al (2002) Prevalence of Q-T interval dispersion in type 1 diabetes and its relation with cardiac ischemia: the EURODIAB IDDM Complications Study Group. Diabetes Care 25:702–707. doi:10.2337/diacare.25.4.702

    Article  PubMed  Google Scholar 

  38. Earle KA, Mishra B, Morocutti A, Barnes D, Chambers J, Viberti GC (2000) QT dispersion in microalbuminuric Type 1 diabetic patients without myocardial ischemia. J Diabetes Complicat 14:277–280. doi:10.1016/S1056-8727(00)00123-9

    Article  CAS  PubMed  Google Scholar 

  39. Veglio M, Bruno G, Borra M et al (2002) Prevalence of increased QT interval duration and dispersion in type 2 diabetic patients and its relationship with coronary heart disease: a population-based cohort. J Intern Med 251:317–324. doi:10.1046/j.1365-2796.2002.00955.x

    Article  CAS  PubMed  Google Scholar 

  40. Annapurna A, Reddy CS, Akondi RB, Rao SRC (2009) Cardioprotective actions of two bioflavonoids, quercetin and rutin, in experimental myocardial infarction in both normal and streptozotocin-induced type I diabetic rats. J Pharm Pharmacol 61:1365–1374. doi:10.1211/jpp/61.10.0014

    Article  CAS  PubMed  Google Scholar 

  41. Murdoch CE, Zhang M, Cave AC, Shah AM (2006) NADPH oxidase-dependent redox signalling in cardiac hypertrophy, remodelling and failure. Cardiovasc Res 71:208–215. doi:10.1016/j.cardiores.2006.03.016

    Article  CAS  PubMed  Google Scholar 

  42. Park JY, Ryu SK, Choi JW et al (2014) Association of inflammation, myocardial fibrosis and cardiac remodelling in patients with mild aortic stenosis as assessed by biomarkers and echocardiography. Clin Exp Pharmacol Physiol 41:185–191. doi:10.1111/1440-1681.12206

    Article  CAS  PubMed  Google Scholar 

  43. Zhang WB, Du QJ, Li H et al (2012) The therapeutic effect of rosuvastatin on cardiac remodelling from hypertrophy to fibrosis during the end-stage hypertension in rats. J Cell Mol Med 16:2227–2237. doi:10.1111/j.1582-4934.2012.01536.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Delhi Institute of Pharmaceutical Sciences and Research (DIPSAR), University of Delhi, Pushp Vihar Sec-3, New Delhi, 110017, India

    Ravi Saklani, Suresh Kumar Gupta, Sushma Srivastava & Rajani Mathur

  2. Mahatma Gandhi Memorial Medical College, Indore, India

    Ipseeta Ray Mohanty

  3. Tufts University, Boston, USA

    Binit Kumar

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  1. Ravi Saklani
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  2. Suresh Kumar Gupta
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Correspondence to Suresh Kumar Gupta.

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Saklani, R., Gupta, S.K., Mohanty, I.R. et al. Cardioprotective effects of rutin via alteration in TNF-α, CRP, and BNP levels coupled with antioxidant effect in STZ-induced diabetic rats. Mol Cell Biochem 420, 65–72 (2016). https://doi.org/10.1007/s11010-016-2767-1

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