Skip to main content
SpringerLink
Log in

Role of Nitric Oxide Synthases in Doxorubicin-Induced Cardiomyopathy

  • Chapter
  • First Online:
Nitric Oxide: From Research to Therapeutics

Part of the book series: Advances in Biochemistry in Health and Disease ((ABHD,volume 22))

  • 380 Accesses

Abstract

Since the discovery of Doxorubicin (Dox), its safe use is under intense discussion due to its cardiotoxic side effects manifested in patients at different times during the treatment or even after years of treatment. Several therapeutic approaches to replace conventional Dox or use of other drugs in combination have exhausted the clinicians and researchers without much success. When the replacement strategies failed to show any rigor, a better understanding of Doxorubicin’s mechanism of action seemed like the only gateway to the discovery of a new targeted therapeutic approach. An increase in reactive oxygen species and the resultant oxidative stress as the mechanism of Dox-induced cardiomyopathy, proposed by us as well as others has gained some traction. However, this explanation has not been enough to alleviate concerns with Dox and we are still in search for a solution for its safe use. More recently, our laboratory and others have also shown the importance of nitrosative stress. Furthermore, we have shown that Vitamin C not only mitigates nitrosative stress but it also modulates Dox-induced cardiotoxic changes in isolated cardiomyocytes as well as in whole animals exposed to Dox. The present review chapter focusses on the mechanism of Dox-induced nitrosative stress and the role of Vitamin C in mitigating the cardiotoxic effects of Dox.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Arcamone F, Cossinellie G, Fantini G, Grein A, Orezzi P, Pol C, Spalla C (1969) Adriamycin, 14-hydroxydaunomycin, a new antitumor antibiotic from S. peucetius var.caesius. Biotechnol Bioeng 11:1101–1110

    Article  CAS  PubMed  Google Scholar 

  2. Lefrak EA, Pitha S, Rosenheim JA, Gottlieb A (1973) A clinico-pathologic analysis of adriamycin cardiotoxicity. Cancer 32:302–314

    Article  CAS  PubMed  Google Scholar 

  3. Singal PK, Iliskovic N (1998) Doxorubicin-induced cardiomyopathy. N Engl J Med 339:900–905

    Article  CAS  PubMed  Google Scholar 

  4. Singal PK, Iliskovic N, Li T, Kumar D (1997) Adriamycin cardiomyopathy: pathophysiology and prevention. FASEB J 11:931–936

    Article  CAS  PubMed  Google Scholar 

  5. Singal PK, Olweny C, Li T (1999) Doxorubicin-induced cardiomyopathy: Correspondence. New Engl J Med 340:655

    Google Scholar 

  6. Lehenbauer Ludke AR, Al-Shudiefat AA, Dhingra S, Jassal DS, Singal PK (2009) A concise description of cardioprotective strategies in doxorubicin-induced cardiotoxicity. Can J Physiol Pharmacol 87:756–763

    Google Scholar 

  7. Chambers JT, Chambers SK, Kohorn EI, Carcangiu ML, Schwartz PE (1996) Uterine papillary serous carcinoma treated with intraperitoneal cisplatin and intravenous doxorubicin and cyclophosphamide. Gynecol Oncol 60:438–442

    Article  CAS  PubMed  Google Scholar 

  8. Weiss RB (1992) The anthracyclines: will we ever find a better doxorubicin? Semin Oncol 19:670–686

    CAS  PubMed  Google Scholar 

  9. Van Tine BA, Agulnik M, Olson RD, Walsh GM, Klausner A, Frank NE, Talley TT, Milhem MM (2019) A phase II clinical study of 13-deoxy, 5-iminodoxorubicin (GPX-150) with metastatic and unresectable soft tissue sarcoma. Cancer Med 8:2994–3003

    Article  PubMed  PubMed Central  Google Scholar 

  10. Ngan YH, Gupta M (2016) A comparison between liposomal and nonliposomal formulations of doxorubicin in the treatment of cancer: An updated review. Arch Pharm Pract 7:1–13

    Article  Google Scholar 

  11. Zhao N, Woodle MC, Mixson AJ (2018) Advances in delivery systems for doxorubicin. J Nanomed Nanotechnol 9:519

    Article  PubMed  PubMed Central  Google Scholar 

  12. Chun C, Lee SM, Kim CW, Hong KY, Kim SY, Yang HK, Song SC (2009) Doxorubicin-polyphosphazene conjugate hydrogels for locally controlled delivery of cancer therapeutics. Biomaterials 30:4752–4762

    Article  CAS  PubMed  Google Scholar 

  13. Wu W, Chen H, Shan F, Zhou J, Sun X, Zhang L, Gong T (2014) A novel doxorubicin-loaded in situ forming gel based high concentration of phospholipid for intratumoral drug delivery. Mol Pharm 11:3378–3385

    Article  CAS  PubMed  Google Scholar 

  14. Lipshultz SE, Colan SD, Gelber RD, Perez-Atayde AR, Sallan SE, Sanders SP (1991) Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med 324:808–815

    Google Scholar 

  15. Arai M, Yoguchi A, Takizawa T, Yokoyama T, Kanda T, Kurabayashi M, Nagai R (2000) Mechanism of doxorubicin-induced inhibition of sarcoplasmic reticulum Ca(2+)-ATPase gene transcription. Circ Res 86:8–14

    Article  CAS  PubMed  Google Scholar 

  16. Ludke AR, Sharma AK, Akolkar G, Bajpai G, Singal PK (2012) Downregulation of vitamin C transporter SVCT-2 in doxorubicin-induced cardiomyocyte injury. Am J Physiol Cell Physiol 303:C645–C653

    Article  CAS  PubMed  Google Scholar 

  17. Pacher P, Obrosova IG, Mabley JG, Szabo C (2005a) Role of nitrosative stress and peroxynitrite in the pathogenesis of diabetic complications. Emerging new therapeutical strategies. Curr Med Chem 12:267–275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Pacher P, Schulz R, Liaudet L, Szabo C (2005b) Nitrosative stress and pharmacological modulation of heart failure. Trends Pharcol Sci 26:302–310

    Article  CAS  Google Scholar 

  19. Szabo C (2009) Role of nitrosative stress in the pathogenesis of diabetic vascular dysfunction. Br J Pharmacol 156:713–727

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Akolkar G, Bagchi AK, Ayyappan P, Jassal DS, Singal PK (2017) Doxorubicin induced nitrosative stress is mitigated by vitamin C via the modulation of nitric oxide synthases. Am J Physiol Cell Physiol 312:418–427

    Article  Google Scholar 

  21. Akolkar G, da Silva DD, Ayyappan P, Bagchi AK, Jassal DS, Salemi VM, Irigoyen MC, Singal PK (2017) Vitamin C mitigates oxidative/nitrosative stress and inflammation in doxorubicin-induced cardiomyopathy. Am J Physiol Heart Circ Physiol 313:H795–H809

    Article  CAS  PubMed  Google Scholar 

  22. Hare JM, Stamler JS (2005) NO/redox disequilibrium in the failing heart and cardiovascular system. J Clin Invest 115:509–517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Mukhopadhyay P, Rajesh M, Batkai S, Kashiwaya Y, Hasko G, Liaudet L, Szabo C, Pacher P (2009) Role of superoxide, nitric oxide, and peroxynitrite in doxorubicin-induced cell death in vivo and in vitro. Am J Physiol Heart Circ Physiol 296:H1466–H1483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lancaster JR (2006) Nitroxidative, nitrosative, and nitrative stress: Kinetic predictions of reactive nitrogen species chemistry under biological conditions. Chem Res Toxicol 19:1160–1174

    Article  CAS  PubMed  Google Scholar 

  25. Weinstein DM, Mihm MJ, Bauer JA (2000) Cardiac peroxynitrite formation and left ventricular dysfunction following doxorubicin treatment in mice. J Pharmacol Exp Therap 294:396–401

    CAS  Google Scholar 

  26. Pacher P, Szabo C (2006) Role of peroxynitrite in the pathogenesis of cardiovascular complications of diabetes. Curr Opin Pharmacol 6:136–141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Salvemini D, Doyle TM, Cuzzocrea S (2006) Superoxide, peroxynitrite and oxidative/nitrative stress in inflammation. Biochem Soc Trans 34:965–970

    Article  CAS  PubMed  Google Scholar 

  28. Turko IV, Murad F (2002) Protein nitration in cardiovascular diseases. Pharmacol Rev 54:619–634

    Article  CAS  PubMed  Google Scholar 

  29. Levrand S, Vannay-Bouchiche C, Pesse B, Pacher P, Feihl F, Waeber B, Liaudet L (2006) Peroxynitrite is a major trigger of cardiomyocyte apoptosis in vitro and in vivo. Free Rad Biol Med 41:886–895

    Article  CAS  PubMed  Google Scholar 

  30. Brown GC (2001) Regulation of mitochondrial respiration by nitric oxide inhibition of cytochrome c oxidase. Biochim Biophys Acta 1504:46–57

    Article  CAS  PubMed  Google Scholar 

  31. MacMillan-Crow LA, Crow JP, Kerby JD, Beckman JS, Thompson JA (1996) Nitration and inactivation of manganese superoxide dismutase in chronic rejection of human renal allografts. Proc Natl Acad Sci 93:11853–11858

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Han YJ, Kwon YG, Chung HT, Lee SK, Simmons RL, Billiar TR, Kim YM (2001) Antioxidant enzymes suppress nitric oxide production through the inhibition of NF-kappa B activation: role of H(2)O(2) and nitric oxide in inducible nitric oxide synthase expression in macrophages. Nitric Oxide 5:504–513

    Article  CAS  PubMed  Google Scholar 

  33. Mihm MJ, Yu F, Weinstein DM, Reiser PJ, Bauer JA (2002) Intracellular distribution of peroxynitrite during doxorubicin cardiomyopathy: evidence for selective impairment of myofibrillar creatine kinase. Brit J Pharmacol 135:581–588

    Article  CAS  Google Scholar 

  34. Ungvari Z, Gupte SA, Recchia FA, Batkai S, Pacher P (2005) Role of oxidative-nitrosative stress and downstream pathways in various forms of cardiomyopathy and heart failure. Curr Vasc Pharmacol 3:221–229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Cassuto J, Dou H, Czikora I, Szabo A, Patel VS, Kamath V, Belin de Chantemele E, Feher A, Romero MJ, Bagi Z (2014) Peroxynitrite disrupts endothelial caveolae leading to eNOS uncoupling and diminished flow-mediated dilation in coronary arterioles of diabetic patients. Diabetes 63:1381–1393

    Google Scholar 

  36. Bruckdorfer R (2005) The basics about nitric oxide. Mol Aspects Med 26:3–31

    Article  CAS  PubMed  Google Scholar 

  37. Bian K, Murad F (2014) What is next in nitric oxide research? from cardiovascular system to cancer biology. Nitric Oxide 43:3–7

    Article  CAS  PubMed  Google Scholar 

  38. Liu VW, Huang PL (2008) Cardiovascular roles of nitric oxide: a review of insights from nitric oxide synthase gene disrupted mice. Cardiovasc Res 77:19–29

    CAS  PubMed  Google Scholar 

  39. Bian K, Doursout MF, Murad F (2008) Vascular system: role of nitric oxide in cardiovascular diseases. J Clins Hypertens 10:304–310

    Article  CAS  Google Scholar 

  40. Katsuki S, Arnold W, Mittal C, Murad F (1977) Stimulation of guanylate cyclase by sodium nitroprusside, nitroglycerin and nitric oxide in various tissue preparations and comparison to the effects of sodium azide and hydroxylamine. J Cyclic Nucleotide Res 3:23–35

    CAS  PubMed  Google Scholar 

  41. Furchgott RF, Zawadzki JV (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288:373–376

    Article  CAS  PubMed  Google Scholar 

  42. Colasanti M, Suzuki H (2000) The dual personality of NO. Trends Pharmacol Sci 21:249–252

    Article  CAS  PubMed  Google Scholar 

  43. Aktan F (2004) iNOS-mediated nitric oxide production and its regulation. Life Sci 75:639–653

    Article  CAS  PubMed  Google Scholar 

  44. Mocellin S, Bronte V, Nitti D (2007) Nitric oxide, a double edged sword in cancer biology: searching for therapeutic opportunities. Med Res Rev 27:317–352

    Article  CAS  PubMed  Google Scholar 

  45. Villanueva C, Giulivi C (2010) Subcellular and cellular locations of nitric oxide synthase isoforms as determinants of health and disease. Free Rad Biol Med 49:307–316

    Article  CAS  PubMed  Google Scholar 

  46. Massion PB, Feron O, Dessy C, Balligand JL (2003) Nitric oxide and cardiac function: ten years after, and continuing. Circ Res 93:388–398

    Article  CAS  PubMed  Google Scholar 

  47. Ziolo MT, Kohr MJ, Wang H (2008) Nitric oxide signaling and the regulation of myocardial function. J Mol Cell Cardiol 45:625–632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Singh S, Gupta AK (2011) Nitric oxide: role in tumour biology and iNOS/NO-based anticancer therapies. Cancer Chemother Pharmacol 67:1211–1224

    Article  CAS  PubMed  Google Scholar 

  49. Forstermann U, Sessa WC (2012) Nitric oxide synthases: regulation and function. Eur Heart J 33:837a–837d

    Article  Google Scholar 

  50. Alderton WK, Cooper CE, Knowles RG (2001) Nitric oxide synthases: structure, function and inhibition. Biochem J 357:593–615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Heller R, Unbehaun A, Schellenberg B, Mayer B, Werner-Felmayer G, Werner ER (2001) L-ascorbic acid potentiates endothelial nitric oxide synthesis via a chemical stabilization of tetrahydrobiopterin. J Biol Chem 276:40–47

    Google Scholar 

  52. Alp NJ, Channon KM (2004) Regulation of endothelial nitric oxide synthase by tetrahydrobiopterin in vascular disease. Arterioscler Thromb Vasc Biol 24:413–420

    Article  CAS  PubMed  Google Scholar 

  53. Channon KM (2004) Tetrahydrobiopterin: regulator of endothelial nitric oxide synthase in vascular disease. Trends Cardiovasc Med 14:323–327

    Article  CAS  PubMed  Google Scholar 

  54. Knowles RG, Moncada S (1994) Nitric oxide synthases in mammals. Biomed J 298:249–258

    CAS  Google Scholar 

  55. Fleming I (2010) Molecular mechanisms underlying the activation of eNOS. Pflugers Arch 459:793–806

    Article  CAS  PubMed  Google Scholar 

  56. Fleming I, Schulz C, Fichtlscherer B, Kemp BE, Fisslthaler B, Busse R (2003) AMP-activated protein kinase (AMPK) regulates the insulin-induced activation of the nitric oxide synthase in human platelets. J Thromb Haemost 90:863–871

    Article  CAS  Google Scholar 

  57. Lin MI, Fulton D, Babbitt R, Fleming I, Busse R, Pritchard KA Jr, Sessa WC (2003) Phosphorylation of threonine 497 in endothelial nitric-oxide synthase coordinates the coupling of L-arginine metabolism to efficient nitric oxide production. J Biol Chem 278:44719–44726

    Article  CAS  PubMed  Google Scholar 

  58. Ladurner A, Schmitt CA, Schachner D, Atanasov AG, Werner ER, Dirsch VM, Heiss EH (2012) Ascorbate stimulates endothelial nitric oxide synthase enzyme activity by rapid modulation of its phosphorylation status. Free Radic Biol Med 52:2082–2090

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Xu L, Eu JP, Meissner G, Stamler JS (1998) Activation of the cardiac calcium release channel (ryanodine receptor) by poly-S-nitrosylation. Science 279:234–237

    Article  CAS  PubMed  Google Scholar 

  60. Umar S, van der Laarse A (2010) Nitric oxide and nitric oxide synthase isoforms in the normal, hypertrophic, and failing heart. Mol Cell Biochem 333:191–201

    Article  CAS  PubMed  Google Scholar 

  61. Gratton JP, Fontana J, O’Connor DS, Garcia-Cardena G, McCabe TJ, Sessa WC (2000) Reconstitution of an endothelial nitric-oxide synthase (eNOS), hsp90, and caveolin-1 complex in vitro. Evidence that hsp90 facilitates calmodulin stimulated displacement of eNOS from caveolin-1. J Biol Chem 275:22268–22272

    Google Scholar 

  62. Drab M, Verkade P, Elger M, Kasper M, Lohn M, Lauterbach B, Menne J et al (2001) Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice. Science 293:2449–2452

    Article  CAS  PubMed  Google Scholar 

  63. Treuer AV, Gonzalez DR (2015) Nitric oxide synthases, S-nitrosylation and cardiovascular health: from molecular mechanisms to therapeutic opportunities (review). Mol Med Rep 11:1555–1565

    Article  CAS  PubMed  Google Scholar 

  64. Feron O (2006) Role of caveolin in angiogenesis and vasculogenesis processes: therapeutic implications in ischemic diseases and cancerology. Bull Mem Acad R Med Belg 161:290–291

    Google Scholar 

  65. Chen W, Xiao H, Rizzo AN, Zhang W, Mai Y, Ye ME (2014) Endothelial nitric oxide synthase dimerization is regulated by heat shock protein 90 rather than by phosphorylation. PLoS ONE 9:e105479

    Article  PubMed  PubMed Central  Google Scholar 

  66. Cai H, Harrison DG (2000) Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 87:840–844

    Article  CAS  PubMed  Google Scholar 

  67. d’Uscio LV, Milstien S, Richardson D, Smith L, Katusic ZS (2003) Long-term vitamin C treatment increases vascular tetrahydrobiopterin levels and nitric oxide synthase activity. Circ Res 92:88–95

    Article  CAS  PubMed  Google Scholar 

  68. Satoh M, Fujimoto S, Haruna Y, Arakawa S, Horike H, Komai N, Sasaki T, Tsujioka K, Makino H, Kashihara N (2005) NAD(P)H oxidase and uncoupled nitric oxide synthase are major sources of glomerular superoxide in rats with experimental diabetic nephropathy. Am J Physiol Renal Physiol 288:F1144–F1152

    Article  CAS  PubMed  Google Scholar 

  69. Ziolo MT, Bers DM (2003) The real estate of NOS signaling: Location, location, location. Circ Res 92:1279–1281

    Article  CAS  PubMed  Google Scholar 

  70. Ashley EA, Sears CE, Bryant SM, Watkins HC, Casadei B (2002) Cardiac nitric oxide synthase 1 regulates basal and beta-adrenergic contractility in murine ventricular myocytes. Circulation 105:3011–3016

    Article  CAS  PubMed  Google Scholar 

  71. Hibbs JB Jr (1991) Synthesis of nitric oxide from L-arginine: a recently discovered pathway induced by cytokines with antitumour and antimicrobial activity. Res Immunol 142:596–598

    Article  Google Scholar 

  72. Rao VA, Zhang J, Klein SR, Espandiari P, Knapton A, Dickey JS et al (2011) The iron chelator Dp44mT inhibits the proliferation of cancer cells but fails to protect from doxorubicin-induced cardiotoxicity in spontaneously hypertensive rats. Cancer Chemother Pharmacol 68:1125–1134

    Article  CAS  PubMed  Google Scholar 

  73. Xia YF, Liu LP, Zhong CP, Geng JG (2001) NF-kappaB activation for constitutive expression of VCAM-1 and ICAM-1 on B lymphocytes and plasma cells. Biochem Biophys Res Commun 289:851–856

    Article  CAS  PubMed  Google Scholar 

  74. Kroncke KD, Fehsel K, Kolb-Bachofen V (1997) Nitric oxide: cytotoxicity versus cytoprotection–how, why, when, and where? Nitric Oxide 1:107–120

    Article  CAS  PubMed  Google Scholar 

  75. De Alba J, Cardenas A, Moro MA, Leza JC, Lorenzo P, Lizasoain I (1999) Use of brain slices in the study of pathogenic role of inducible nitric oxide synthase in cerebral ischemia-reperfusion. Gen Pharmacol 32:577–581

    Article  PubMed  Google Scholar 

  76. Murad F (2011) Nitric oxide: The coming of the second messenger. Rambam Maimonides Med J 2:e0038

    Article  PubMed  PubMed Central  Google Scholar 

  77. Bryan NS, Bian K, Murad F (2009) Discovery of the nitric oxide signaling pathway and targets for drug development. Front Biosci 14:1–18

    Article  CAS  Google Scholar 

  78. Lima B, Forrester MT, Hess DT, Stamler JS (2010) S-nitrosylation in cardiovascular signaling. Circ Res 106:633–646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Irie T, Sips PY, Kai S, Kida K, Ikeda K, Hirai S, Moazzami K et al (2015) S-nitrosylation of calcium-handling proteins in cardiac adrenergic signaling and hypertrophy. Circ Res 117:793–803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Kouti L, Noroozian M, Akhondzadeh S, Abdollahi M, Javadi MR, Faramarzi MA, Mousavi S, Ghaeli P (2013) Nitric oxide and peroxynitrite serum levels in Parkinson’s disease: correlation of oxidative stress and the severity of the disease. Eur Rev Med Pharmacol Sci 17:964–970

    CAS  PubMed  Google Scholar 

  81. Ben Anes A, Fetoui H, Bchir S, Ben Nasr H, Chahdoura H, Chabchoub E, Yacoub S, et al (2014) Increased oxidative stress and altered levels of nitric oxide and peroxynitrite in Tunisian patients with chronic obstructive pulmonary disease: Correlation with disease severity and airflow obstruction. Biol Trace Elem Res 161:2031

    Google Scholar 

  82. Islam BU, Habib S, Ahmad P, Allarakha S, Moinuddin AA (2015) Pathophysiological role of peroxynitrite induced DNA damage in human diseases: A special focus on poly (ADP-ribose) polymerase (PARP). Indian J Clin Biochem 30:368–385

    Article  PubMed  PubMed Central  Google Scholar 

  83. Sayed-Ahmed MM, Khattab MM, Gad MZ, Osman AM (2001) Increased plasma endothelin-1 and cardiac nitric oxide during doxorubicin-induced cardiomyopathy. Pharmacol Toxicol 89:140–144

    Article  CAS  PubMed  Google Scholar 

  84. Ferdinandy P, Danial H, Ambrus I, Rothery RA, Schulz R (2000) Peroxynitrite is a major contributor to cytokine-induced myocardial contractile failure. Circ Res 87:241–247

    Article  CAS  PubMed  Google Scholar 

  85. Beltran B, Orsi A, Clementi E, Moncada S (2000) Oxidative stress and S-nitrosylation of proteins in cells. Br J Pharmacol 129:953–960

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Iwakiri Y (2011) S-nitrosylation of proteins: A new insight into endothelial cell function regulated by eNOS-derived NO. Nitric Oxide 25:95–101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Ravi K, Brennan LA, Levic S, Ross PA, Black SM (2004) S-nitrosylation of endothelial nitric oxide synthase is associated with monomerization and decreased enzyme activity. Proc Natl Acad Sci 101:2619–2624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Pacher P, Liaudet L, Bai P, Mabley JG, Kaminski PM, Virag L, Deb A et al (2003) Potent metalloporphyrin peroxynitrite decomposition catalyst protects against the development of doxorubicin-induced cardiac dysfunction. Circulation 107:896–904

    Article  CAS  PubMed  Google Scholar 

  89. Andreadou I, Sigala F, Iliodromitis EK, Papaefthimiou M, Sigalas C, Aligiannis N, Savvari P, Gorgoulis V, Papalabros E, Kremastinos DT (2007) Acute doxorubicin cardiotoxicity is successfully treated with the phytochemical oleuropein through suppression of oxidative and nitrosative stress. J Mol Cell Cardiol 42:549–558

    Article  CAS  PubMed  Google Scholar 

  90. Andreadou I, Mikros E, Ioannidis K, Sigala F, Naka K, Kostidis S, Farmakis D, Tenta R, Kavantzas N, Bibli SI, Gikas E, Skaltsounis L, Kremastinos DT, Iliodromitis EK (2014) Oleuropein prevents doxorubicin-induced cardiomyopathy interfering with signaling molecules and cardiomyocyte metabolism. J Mol Cell Cardiol 69:4–16

    Article  CAS  PubMed  Google Scholar 

  91. Oktem G, Uysal A, Oral O, Sezer ED, Olukman M, Erol A, Akgur SA, Bilir A (2012) Resveratrol attenuates doxorubicin-induced cellular damage by modulating nitric oxide and apoptosis. Exp Toxicol Pathol 64:471–479

    Article  CAS  PubMed  Google Scholar 

  92. Andrew PJ, Mayer B (1999) Enzymatic function of nitric oxide synthases. Cardiovasc Res 43:521–531

    Article  CAS  PubMed  Google Scholar 

  93. Zou MH, Hou XY, Shi CM, Nagata D, Walsh K, Cohen RA (2002) Modulation by peroxynitrite of akt- and AMP-activated kinase-dependent Ser1179 phosphorylation of endothelial nitric oxide synthase. J Biol Chem 277:32552–32557

    Article  CAS  PubMed  Google Scholar 

  94. Yang YM, Huang A, Kaley G, Sun D (2009) eNOS uncoupling and endothelial dysfunction in aged vessels. Am J Physiol Heart Circ Physiol 297:H1829–H1836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Gamez-Mendez AM, Vargas-Robles H, Rios A, Escalante B (2015) Oxidative stress-dependent coronary endothelial dysfunction in obese mice. PLoS ONE 10:e0138609

    Google Scholar 

  96. Neilan TG, Blake SL, Ichinose F, Raher MJ, Buys ES, Jassal DS, Furutani E et al (2007) Disruption of nitric oxide synthase 3 protects against the cardiac injury, dysfunction, and mortality induced by doxorubicin. Circulation 116:506–514

    Article  CAS  PubMed  Google Scholar 

  97. Deng S, Kruger A, Schmidt A, Metzger A, Yan T, Godtel-Armbrust U, Hasenfuss G, Brunner F, Wojnowski L (2009) Differential roles of nitric oxide synthase isozymes in cardiotoxicity and mortality following chronic doxorubicin treatment in mice. Naunyn-Schmiedeberg’s Arch Pharmacol 380:25–34

    Article  CAS  Google Scholar 

  98. Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM (1999) Activation of nitric oxide synthase in endothelial cells by akt-dependent phosphorylation. Nature 399:601–605

    Article  CAS  PubMed  Google Scholar 

  99. Aldieri E, Bergandi L, Riganti C, Costamagna C, Bosia A, Ghigo D (2002) Doxorubicin induces an increase of nitric oxide synthesis in rat cardiac cells that is inhibited by iron supplementation. Tox Appl Pharmacol 185:85–90

    Article  CAS  Google Scholar 

  100. Ropelle ER, Pauli JR, Cintra DE, da Silva AS, De Souza CT, Guadagnini D, Carvalho BM et al (2013) Targeted disruption of inducible nitric oxide synthase protects against aging, S-nitrosation, and insulin resistance in muscle of male mice. Diabetes 62:466–470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Feng Q, Lu X, Jones DL, Shen J, Arnold AM (2001) Increased inducible nitric oxide synthase expression contributes to myocardial dysfunction and higher mortality after myocardial infarction in mice. Circulation 104:700–704

    Article  CAS  PubMed  Google Scholar 

  102. Zhu J, Zhang J, Zhang L, Du R, Xiang D, Wu M, Zhang R, Han W (2011) Interleukin-1 signaling mediates acute doxorubicin-induced cardiotoxicity. Biomed Pharmacother 65:481–485

    Article  CAS  PubMed  Google Scholar 

  103. Ing DJ, Zang J, Dzau VJ, Webster KA, Bishopric NH (1999) Modulation of cytokine-induced cardiac myocyte apoptosis by nitric oxide, Bak, and Bcl-x. Circ Res 84:21–33

    Article  CAS  PubMed  Google Scholar 

  104. Bowie AG, O’Neill LA (2000) Vitamin C inhibits NF-kappa B activation by TNF via the activation of p38 mitogen-activated protein kinase. J Immunol 165:7180–7188

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Dr. P. K. Singal is the holder of the Dr. Naranjan S. Dhalla Chair in Cardiovascular Research supported by the St. Boniface Hospital Foundation.

Author information

Authors and Affiliations

  1. University of Ottawa Heart Institute, Ottawa, ON, K1Y 4W7, Canada

    Gauri Akolkar

  2. Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, R3T 2N2, Canada

    Akshi Malik, Ashim K. Bagchi & Pawan K. Singal

  3. Division of Metabolic and Cardiovascular Sciences, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, 32816, USA

    Dinender K. Singla

  4. Northern Ontario School of Medicine, Lakehead University, Thunder Bay, ON, P7B 5E1, Canada

    Neelam Khaper

Authors
  1. Gauri Akolkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Akshi Malik
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ashim K. Bagchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dinender K. Singla
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Neelam Khaper
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Pawan K. Singal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pawan K. Singal .

Editor information

Editors and Affiliations

  1. Department of Pharmacology, Hamdard Institute of Medical Sciences and Research, Hamdard University, New Delhi, India

    Arunabha Ray

  2. Department of Pharmacology, Vallabhbhai Patel Chest Institute, University of Delhi, New Delhi, India

    Kavita Gulati

Rights and permissions

Reprints and permissions

Copyright information

© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Akolkar, G., Malik, A., Bagchi, A.K., Singla, D.K., Khaper, N., Singal, P.K. (2023). Role of Nitric Oxide Synthases in Doxorubicin-Induced Cardiomyopathy. In: Ray, A., Gulati, K. (eds) Nitric Oxide: From Research to Therapeutics. Advances in Biochemistry in Health and Disease, vol 22. Springer, Cham. https://doi.org/10.1007/978-3-031-24778-1_7

Download citation

Publish with us

Policies and ethics

Search

Navigation