Role of Oxidative Stress, Mitochondrial Dysfunction, and Autophagy in Cardiovascular Disease: Its Pathogenesis and Amelioration by Different Small Natural Molecules

  • Sharmistha Chatterjee
  • Uday Hossain
  • Parames C. SilEmail author


The biggest cause of global mortality today is cardiovascular diseases. Not only old people, but even the younger generation gets afflicted now. This chapter will focus on the role of oxidative stress, mitochondrial dysfunction, and autophagy on the pathogenesis of the various forms of cardiovascular diseases including heart failure, atherosclerosis, hypertension, myocardial infarction, and ischemia-reperfusion injury. Various cell signaling pathways get modulated under external or internal stress stimuli to induce ROS which begets the oxidative stress condition. The antioxidant defense mechanisms by which the delicate balance between prooxidants and antioxidants in the cell is maintained in equilibrium get disrupted, and the structural and functional entities of the cell collapse. Mitochondrial dysfunction is directly implicated in the above process, as it is both the cause and outcome of oxidative stress. When dysfunctional mitochondria accumulate inside the cell, autophagy comes to the rescue. But excessive autophagy again is a cause of concern as it paves the way for a second type of programmed cell death, distinct from apoptosis. Antioxidants have mostly been proven highly effective against the plethora of cardiovascular diseases, as they have been successful in attenuating the oxidative stress in the vascular cells, as well as that in the myocardial cells, and have restored the physiological conditions close to the normal state. So they have been routed to be important drug leads for the development of effective therapeutics against cardiovascular diseases. With minimal or no toxicity, natural molecules have remained in the forefront to be tested and tried in this regard. So this field has and will continue to have importance in the research fraternity for decades to come.


Cardiovascular diseases Reactive oxygen species Oxidative stress Antioxidant Mitochondrial dysfunction Autophagy Endothelial dysfunction Atherosclerosis Hypertension Myocardial infarction Ischemia-reperfusion Amelioration Small molecules 


  1. 1.
    Kelly BB, Fuster V (2010) Promoting cardiovascular health in the developing world: a critical challenge to achieve global health. National Academies Press, Washington, DCGoogle Scholar
  2. 2.
    Beaglehole R, Bonita R (2008) Global public health: a scorecard. Lancet 372(9654):1988–1996PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Prabhakaran D, Jeemon P, Roy A (2016) Cardiovascular diseases in India: current epidemiology and future directions. Circulation 133(16):1605–1620CrossRefGoogle Scholar
  4. 4.
    Farrugia G, Balzan R (2012) Oxidative stress and programmed cell death in yeast. Front Oncol 2:64PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Matés JM, Segura JA, Alonso FJ, Márquez J (2012) Oxidative stress in apoptosis and cancer: an update. Arch Toxicol 86(11):1649–1665PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Lakshmi SV, Padmaja G, Kuppusamy P, Kutala VK (2009) Oxidative stress in cardiovascular disease. Indian J Biochem Biophys 46(6):421–440PubMedGoogle Scholar
  7. 7.
    Sinha K, Das J, Pal PB, Sil PC (2013) Oxidative stress: the mitochondria-dependent and mitochondria-independent pathways of apoptosis. Arch Toxicol 87(7):1157–1180PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Cabiscol Català E, Tamarit Sumalla J, Ros Salvador J (2000) Oxidative stress in bacteria and protein damage by reactive oxygen species. Int Microbiol 3(1):3–8Google Scholar
  9. 9.
    Biliński T, Litwińska J, Błszczyński M, Bajus A (1989) Superoxide dismutase deficiency and the toxicity of the products of autooxidation of polyunsaturated fatty acids in yeast. Biochim Biophys Acta 1001(1):102–106PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Yakes FM, Van Houten B (1997) Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress. Proc Natl Acad Sci 94(2):514–519PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Matés JM, Segura JA, Alonso FJ, Márquez J (2010) Roles of dioxins and heavy metals in cancer and neurological diseases using ROS-mediated mechanisms. Free Radic Biol Med 49(9):1328–1341PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Halliwell B, Cross CE (1994) Oxygen-derived species: their relation to human disease and environmental stress. Environ Health Perspect 102(Suppl 10):5PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Sies H (1991) Oxidative stress: from basic research to clinical application. Am J Med 91(3):S31–S38CrossRefGoogle Scholar
  14. 14.
    Turrens JF, Boveris A (1980) Generation of superoxide anion by the NADH dehydrogenase of bovine heart mitochondria. Biochem J 191(2):421–427PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Ueda S, Masutani H, Nakamura H, Tanaka T, Ueno M, Yodoi J (2002) Redox control of cell death. Antioxid Redox Signal 4(3):405–414PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Bai H, Hai C, Xi M, Liang X, Liu R (2010) Protective effect of maize silks (Maydis stigma) ethanol extract on radiation-induced oxidative stress in mice. Plant Foods Hum Nutr 65(3):271–276PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Altraja S, Mahlapuu R, Soomets U, Altraja A (2013) Cigarette smoke-induced differential regulation of glutathione metabolism in bronchial epithelial cells is balanced by an antioxidant tetrapeptide UPF1. Exp Toxicol Pathol 65(6):711–717PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Ahmad I, Kumar A, Shukla S, Prasad Pandey H, Singh C (2008) The involvement of nitric oxide in maneb- and paraquat-induced oxidative stress in rat polymorphonuclear leukocytes. Free Radic Res 42(10):849–862PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Morcillo P, Esteban MÁ, Cuesta A (2016) Heavy metals produce toxicity, oxidative stress and apoptosis in the marine teleost fish SAF-1 cell line. Chemosphere 144:225–233PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Pal S, Pal PB, Das J, Sil PC (2011) Involvement of both intrinsic and extrinsic pathways in hepatoprotection of arjunolic acid against cadmium induced acute damage in vitro. Toxicology 283(2–3):129–139PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Pal PB, Pal S, Das J, Sil PC (2012) Modulation of mercury-induced mitochondria-dependent apoptosis by glycine in hepatocytes. Amino Acids 42(5):1669–1683PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Pal PB, Sinha K, Sil PC (2013) Mangiferin, a natural xanthone, protects murine liver in Pb (II) induced hepatic damage and cell death via MAP kinase, NF-κB and mitochondria dependent pathways. PloS one 8(2):e56894PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Manna P, Roy A, Sil PC (2009) Prophylactic role of taurine on arsenic mediated oxidative renal dysfunction via MAPKs/NF-B and mitochondria dependent pathways. Free Radic Res 43(10):995–1007Google Scholar
  24. 24.
    Saha S, Rashid K, Sadhukhan P, Agarwal N, Sil PC (2016) Attenuative role of mangiferin in oxidative stress-mediated liver dysfunction in arsenic-intoxicated murines. Biofactors 42(5):515–532PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Das J, Ghosh J, Manna P, Sil PC (2011) Taurine suppresses doxorubicin-triggered oxidative stress and cardiac apoptosis in rat via up-regulation of PI3-K/Akt and inhibition of p53, p38-JNK. Biochem Pharmacol 81(7):891–909PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Das J, Ghosh J, Manna P, Sil PC (2012) Taurine protects rat testes against doxorubicin-induced oxidative stress as well as p53, Fas and caspase 12-mediated apoptosis. Amino Acids 42(5):1839–1855PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Das J, Sil PC (2012) Taurine ameliorates alloxan-induced diabetic renal injury, oxidative stress-related signaling pathways and apoptosis in rats. Amino Acids 43(4):1509–1523PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Das J, Ghosh J, Roy A, Sil PC (2012) Mangiferin exerts hepatoprotective activity against D-galactosamine induced acute toxicity and oxidative/nitrosative stress via Nrf2–NFκB pathways. Toxicol Appl Pharmacol 260(1):35–47PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Banerjee S, Sinha K, Chowdhury S, Sil PC (2018) Unfolding the mechanism of cisplatin induced pathophysiology in spleen and its amelioration by carnosine. Chem Biol Interact 279:159–170PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Das J, Ghosh J, Manna P, Sil PC (2010) Acetaminophen induced acute liver failure via oxidative stress and JNK activation: protective role of taurine by the suppression of cytochrome P450 2E1. Free Radic Res 44(3):340–355PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Ghosh J, Das J, Manna P, Sil PC (2011) The protective role of arjunolic acid against doxorubicin induced intracellular ROS dependent JNK-p38 and p53-mediated cardiac apoptosis. Biomaterials 32(21):4857–4866PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Bhattacharya S, Gachhui R, Sil PC (2011) Hepatoprotective properties of kombucha tea against TBHP-induced oxidative stress via suppression of mitochondria dependent apoptosis. Pathophysiology 18(3):221–234PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Sarkar MK, Sil PC (2010) Prevention of tertiary butyl hydroperoxide induced oxidative impairment and cell death by a novel antioxidant protein molecule isolated from the herb, Phyllanthus niruri. Toxicol in Vitro 24(6):1711–1719PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Gille G, Sigler K (1995) Oxidative stress and living cells. Folia Microbiol 40(2):131–152CrossRefGoogle Scholar
  35. 35.
    Ghosh M, Das J, Sil PC (2012) D (+) galactosamine induced oxidative and nitrosative stress-mediated renal damage in rats via NF-κB and inducible nitric oxide synthase (iNOS) pathways is ameliorated by a polyphenol xanthone, mangiferin. Free Radic Res 46(2):116–132PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Manna P, Sinha M, Sil PC (2009) Protective role of arjunolic acid in response to streptozotocin-induced type-I diabetes via the mitochondrial dependent and independent pathways. Toxicology 257(1–2):53–63PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Manna P, Das J, Ghosh J, Sil PC (2010) Contribution of type 1 diabetes to rat liver dysfunction and cellular damage via activation of NOS, PARP, IκBα/NF-κB, MAPKs, and mitochondria-dependent pathways: prophylactic role of arjunolic acid. Free Radic Biol Med 48(11):1465–1484PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Bhattacharya S, Manna P, Gachhui R, Sil PC (2013) D-Saccharic acid 1, 4-lactone protects diabetic rat kidney by ameliorating hyperglycemia-mediated oxidative stress and renal inflammatory cytokines via NF-κB and PKC signaling. Toxicol Appl Pharmacol 267(1):16–29PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB (2010) Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med 49(11):1603–1616PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Dai D-F, Rabinovitch PS, Ungvari Z (2012) Mitochondria and cardiovascular aging. Circ Res 110(8):1109–1124PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Kao S-H, Chao H-T, Wei Y-H (1998) Multiple deletions of mitochondrial DNA are associated with the decline of motility and fertility of human spermatozoa. Mol Hum Reprod 4(7):657–666PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Clayton DA (1984) Transcription of the mammalian mitochondrial genome. Annu Rev Biochem 53(1):573–594PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Ballinger SW (2005) Mitochondrial dysfunction in cardiovascular disease. Free Radic Biol Med 38(10):1278–1295PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Klionsky DJ, Emr SD (2000) Autophagy as a regulated pathway of cellular degradation. Science 290(5497):1717–1721PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Yoshimori T (2004) Autophagy: a regulated bulk degradation process inside cells. Biochem Biophys Res Commun 313(2):453–458PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Levine B, Klionsky DJ (2004) Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 6(4):463–477PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Yorimitsu T, Klionsky DJ (2005) Autophagy: molecular machinery for self-eating. Cell Death Differ 12(S2):1542PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Debnath J, Baehrecke EH, Kroemer G (2005) Does autophagy contribute to cell death? Autophagy 1(2):66–74PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Levine B, Yuan J (2005) Autophagy in cell death: an innocent convict? J Clin Invest 115(10):2679–2688PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Edinger AL, Thompson CB (2004) Death by design: apoptosis, necrosis and autophagy. Curr Opin Cell Biol 16(6):663–669PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Bobryshev YV (2006) Monocyte recruitment and foam cell formation in atherosclerosis. Micron 37(3):208–222PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Powers SK, Ji LL, Kavazis AN, Jackson MJ (2011) Reactive oxygen species: impact on skeletal muscle. Compr Physiol 1(2):941–969PubMedPubMedCentralGoogle Scholar
  53. 53.
    Espinosa A, Henriquez-Olguin C, Jaimovich E (2016) Reactive oxygen species and calcium signals in skeletal muscle: A crosstalk involved in both normal signaling and disease. Cell Calcium 60(3):172–179PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Johar S, MacCarthy PA, Shah AM (2006) Oxidative stress and cardiovascular disease. In: Oxidative stress, disease and cancer. World Scientific, pp 519–535Google Scholar
  55. 55.
    Lüscher T, Barton M (1997) Biology of the endothelium. Clin Cardiol 20(11 Suppl 2):II-3Google Scholar
  56. 56.
    Landmesser U, Spiekermann S, Dikalov S, Tatge H, Wilke R, Kohler C, Harrison DG, Hornig B, Drexler H (2002) Vascular oxidative stress and endothelial dysfunction in patients with chronic heart failure: role of xanthine-oxidase and extracellular superoxide dismutase. Circulation 106(24):3073–3078PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Park JB, Schiffrin EL (2001) Small artery remodeling is the most prevalent (earliest?) form of target organ damage in mild essential hypertension. J Hypertens 19(5):921–930PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Rizzoni D, Porteri E, Guelfi D, Muiesan ML, Valentini U, Cimino A, Girelli A, Rodella L, Bianchi R, Sleiman I (2001) Structural alterations in subcutaneous small arteries of normotensive and hypertensive patients with non–insulin-dependent diabetes mellitus. Circulation 103(9):1238–1244PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Li J-M, Shah AM (2004) Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology. Am J Physiol Regul Integr Comp Physiol 287(5):R1014–R1030PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Schächinger V, Britten M, Dimmeler S, Zeiher A (2001) NADH/NADPH oxidase p22 phox gene polymorphism is associated with improved coronary endothelial vasodilator function. Eur Heart J 22(1):96–101PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Zalba G, José GS, Beaumont FJ, Fortuño MA, Fortuño A, Díez J (2001) Polymorphisms and promoter overactivity of the p22 phox gene in vascular smooth muscle cells from spontaneously hypertensive rats. Circ Res 88(2):217–222PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Shokoji T, Nishiyama A, Fujisawa Y, Hitomi H, Kiyomoto H, Takahashi N, Kimura S, Kohno M, Abe Y (2003) Renal sympathetic nerve responses to tempol in spontaneously hypertensive rats. Hypertension 41(2):266–273PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Park JB, Touyz RM, Chen X, Schiffrin EL (2002) Chronic treatment with a superoxide dismutase mimetic prevents vascular remodeling and progression of hypertension in salt-loaded stroke-prone spontaneously hypertensive rats. Am J Hypertens 15(1):78–84PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Paravicini TM, Chrissobolis S, Drummond GR, Sobey CG (2004) Increased NADPH-oxidase activity and Nox4 expression during chronic hypertension is associated with enhanced cerebral vasodilatation to NADPH in vivo. Stroke 35(2):584–589PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Touyz RM (2004) Reactive oxygen species, vascular oxidative stress, and redox signaling in hypertension: what is the clinical significance? Hypertension 44(3):248–252PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Rueckschloss U, Quinn MT, Holtz J, Morawietz H (2002) Dose-dependent regulation of NAD (P) H oxidase expression by angiotensin II in human endothelial cells: protective effect of angiotensin II type 1 receptor blockade in patients with coronary artery disease. Arterioscler Thromb Vasc Biol 22(11):1845–1851PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Berry C, Anderson N, Kirk AJ, Dominiczak AF, Mcmurray JJ (2001) Renin angiotensin system inhibition is associated with reduced free radical concentrations in arteries of patients with coronary heart disease. Heart 86(2):217–220PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Morrow JD, Frei B, Longmire AW, Gaziano JM, Lynch SM, Shyr Y, Strauss WE, Oates JA, Roberts LJ (1995) Increase in circulating products of lipid peroxidation (F2-isoprostanes) in smokers—smoking as a cause of oxidative damage. N Engl J Med 332(18):1198–1203PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Reilly MP, Pratico D, Delanty N, DiMinno G, Tremoli E, Rader D, Kapoor S, Rokach J, Lawson J, FitzGerald GA (1998) Increased formation of distinct F2 isoprostanes in hypercholesterolemia. Circulation 98(25):2822–2828PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Yamaguchi Y, Kunitomo M, Haginaka J (2002) Assay methods of modified lipoproteins in plasma. J Chromatogr B 781(1–2):313–330CrossRefGoogle Scholar
  71. 71.
    Warnholtz A, Nickenig G, Schulz E, Macharzina R, Brasen JH, Skatchkov M, Heitzer T, Stasch JP, Griendling KK, Harrison DG (1999) Increased NADH-oxidase–mediated superoxide production in the early stages of atherosclerosis: evidence for involvement of the renin-angiotensin system. Circulation 99(15):2027–2033PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Weiss D, Kools JJ, Taylor WR (2001) Angiotensin II–induced hypertension accelerates the development of atherosclerosis in apoE-deficient mice. Circulation 103(3):448–454PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Ohara Y, Peterson TE, Harrison DG (1993) Hypercholesterolemia increases endothelial superoxide anion production. J Clin Investig 91(6):2546–2551PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Mügge A, Elwell JH, Peterson TE, Hofmeyer TG, Heistad DD, Harrison DG (1991) Chronic treatment with polyethylene-glycolated superoxide dismutase partially restores endothelium-dependent vascular relaxations in cholesterol-fed rabbits. Circ Res 69(5):1293–1300PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Böger RH, Bode-Böger SM, Mügge A, Kienke S, Brandes R, Dwenger A, Frölich JC (1995) Supplementation of hypercholesterolaemic rabbits with L-arginine reduces the vascular release of superoxide anions and restores NO production. Atherosclerosis 117(2):273–284PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Miller FJ, Gutterman DD, Rios CD, Heistad DD, Davidson BL (1998) Superoxide production in vascular smooth muscle contributes to oxidative stress and impaired relaxation in atherosclerosis. Circ Res 82(12):1298–1305PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Praticò D, Tangirala RK, Rader DJ, Rokach J, FitzGerald GA (1998) Vitamin E suppresses isoprostane generation in vivo and reduces atherosclerosis in ApoE-deficient mice. Nat Med 4(10):1189PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Tangirala RK, Praticó D, FitzGerald GA, Chun S, Tsukamoto K, Maugeais C, Usher DC, Puré E, Rader DJ (2001) Reduction of isoprostanes and regression of advanced atherosclerosis by apolipoprotein E. J Biol Chem 276(1):261–266PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Febbraio M, Podrez EA, Smith JD, Hajjar DP, Hazen SL, Hoff HF, Sharma K, Silverstein RL (2000) Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice. J Clin Investig 105(8):1049–1056PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Cyrus T, Witztum JL, Rader DJ, Tangirala R, Fazio S, Linton MF, Funk CD (1999) Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E–deficient mice. J Clin Investig 103(11):1597–1604PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Galis ZS, Sukhova GK, Lark MW, Libby P (1994) Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Investig 94(6):2493–2503PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Faia KL, Davis WP, Marone AJ, Foxall TL (2002) Matrix metalloproteinases and tissue inhibitors of metalloproteinases in hamster aortic atherosclerosis: correlation with in-situ zymography. Atherosclerosis 160(2):325–337PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Dhalla AK, Hill MF, Singal PK (1996) Role of oxidative stress in transition of hypertrophy to heart failure. J Am Coll Cardiol 28(2):506–514CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Nakamura K, Fushimi K, Kouchi H, Mihara K, Miyazaki M, Ohe T, Namba M (1998) Inhibitory effects of antioxidants on neonatal rat cardiac myocyte hypertrophy induced by tumor necrosis factor-alpha and angiotensin II. Circulation 98(8):794–799PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    MacCarthy PA, Grieve DJ, Li JM, Dunster C, Kelly FJ, Shah AM (2001) Impaired endothelial regulation of ventricular relaxation in cardiac hypertrophy: role of reactive oxygen species and NADPH oxidase. Circulation 104(24):2967–2974PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Park YM, Park MY, Suh YL, Park JB (2004) NAD(P)H oxidase inhibitor prevents blood pressure elevation and cardiovascular hypertrophy in aldosterone-infused rats. Biochem Biophys Res Commun 313(3):812–817PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Siwik DA, Pagano PJ, Colucci WS (2001) Oxidative stress regulates collagen synthesis and matrix metalloproteinase activity in cardiac fibroblasts. Am J Physiol Cell Physiol 280(1):C53–C60PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Bendall JK, Cave AC, Heymes C, Gall N, Shah AM (2002) Pivotal role of a gp91(phox)-containing NADPH oxidase in angiotensin II-induced cardiac hypertrophy in mice. Circulation 105(3):293–296CrossRefGoogle Scholar
  89. 89.
    Heymes C, Bendall JK, Ratajczak P, Cave AC, Samuel JL, Hasenfuss G, Shah AM (2003) Increased myocardial NADPH oxidase activity in human heart failure. J Am Coll Cardiol 41(12):2164–2171PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Palace V, Kumar D, Hill MF, Khaper N, Singal PK (1999) Regional differences in non-enzymatic antioxidants in the heart under control and oxidative stress conditions. J Mol Cell Cardiol 31(1):193–202PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Prasad K, Lee P, Mantha SV, Kalra J, Prasad M, Gupta JB (1992) Detection of ischemia-reperfusion cardiac injury by cardiac muscle chemiluminescence. Mol Cell Biochem 115(1):49–58PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Jolly SR, Kane WJ, Bailie MB, Abrams GD, Lucchesi BR (1984) Canine myocardial reperfusion injury. Its reduction by the combined administration of superoxide dismutase and catalase. Circ Res 54(3):277–285PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Temsah RM, Netticadan T, Chapman D, Takeda S, Mochizuki S, Dhalla NS (1999) Alterations in sarcoplasmic reticulum function and gene expression in ischemic-reperfused rat heart. Am J Physiol 277(2 Pt 2):H584–H594PubMedPubMedCentralGoogle Scholar
  94. 94.
    Chen EP, Bittner HB, Davis RD, Van Trigt P, Folz RJ (1998) Physiologic effects of extracellular superoxide dismutase transgene overexpression on myocardial function after ischemia and reperfusion injury. J Thoracic Cardiovasc Surg 115(2):450–458. Discussion 458–459PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Yoshida T, Maulik N, Engelman RM, Ho YS, Das DK (2000) Targeted disruption of the mouse Sod I gene makes the hearts vulnerable to ischemic reperfusion injury. Circ Res 86(3):264–269PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Sethi R, Takeda N, Nagano M, Dhalla NS (2000) Beneficial effects of vitamin E treatment in acute myocardial infarction. J Cardiovasc Pharmacol Ther 5(1):51–58PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Kinugawa S, Tsutsui H, Hayashidani S, Ide T, Suematsu N, Satoh S, Utsumi H, Takeshita A (2000) Treatment with dimethylthiourea prevents left ventricular remodeling and failure after experimental myocardial infarction in mice: role of oxidative stress. Circ Res 87(5):392–398PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Sia YT, Lapointe N, Parker TG, Tsoporis JN, Deschepper CF, Calderone A, Pourdjabbar A, Jasmin JF, Sarrazin JF, Liu P, Adam A, Butany J, Rouleau JL (2002) Beneficial effects of long-term use of the antioxidant probucol in heart failure in the rat. Circulation 105(21):2549–2555PubMedCrossRefPubMedCentralGoogle Scholar
  99. 99.
    Spinale FG (2002) Matrix metalloproteinases: regulation and dysregulation in the failing heart. Circ Res 90(5):520–530PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Cox MJ, Hawkins UA, Hoit BD, Tyagi SC (2004) Attenuation of oxidative stress and remodeling by cardiac inhibitor of metalloproteinase protein transfer. Circulation 109(17):2123–2128PubMedCrossRefPubMedCentralGoogle Scholar
  101. 101.
    Marzetti E, Csiszar A, Dutta D, Balagopal G, Calvani R, Leeuwenburgh C (2013) Role of mitochondrial dysfunction and altered autophagy in cardiovascular aging and disease: from mechanisms to therapeutics. Am J Physiol Heart Circ Physiol 305(4):H459–H476PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Dutta D, Calvani R, Bernabei R, Leeuwenburgh C, Marzetti E (2012) Contribution of impaired mitochondrial autophagy to cardiac aging: mechanisms and therapeutic opportunities. Circ Res 110(8):1125–1138PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Calvani R, Joseph AM, Adhihetty PJ, Miccheli A, Bossola M, Leeuwenburgh C, Bernabei R, Marzetti E (2013) Mitochondrial pathways in sarcopenia of aging and disuse muscle atrophy. Biol Chem 394(3):393–414PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Schafer A, Reichert AS (2009) Emerging roles of mitochondrial membrane dynamics in health and disease. Biol Chem 390(8):707–715PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Benard G, Rossignol R (2008) Ultrastructure of the mitochondrion and its bearing on function and bioenergetics. Antioxid Redox Signal 10(8):1313–1342PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Aon MA, Cortassa S (2012) Mitochondrial network energetics in the heart. Wiley Interdiscip Rev Syst Biol Med 4(6):599–613PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Twig G, Hyde B, Shirihai OS (2008) Mitochondrial fusion, fission and autophagy as a quality control axis: the bioenergetic view. Biochim Biophys Acta 1777(9):1092–1097PubMedCrossRefPubMedCentralGoogle Scholar
  108. 108.
    Chen H, Detmer SA, Ewald AJ, Griffin EE, Fraser SE, Chan DC (2003) Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol 160(2):189–200PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Cipolat S, Martins de Brito O, Dal Zilio B, Scorrano L (2004) OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc Natl Acad Sci USA 101(45):15927–15932PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Smirnova E, Griparic L, Shurland DL, van der Bliek AM (2001) Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol Biol Cell 12(8):2245–2256PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Stojanovski D, Koutsopoulos OS, Okamoto K, Ryan MT (2004) Levels of human Fis1 at the mitochondrial outer membrane regulate mitochondrial morphology. J Cell Sci 117(Pt 7):1201–1210PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Ong SB, Hall AR, Hausenloy DJ (2013) Mitochondrial dynamics in cardiovascular health and disease. Antioxid Redox Signal 19(4):400–414PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Ong SB, Subrayan S, Lim SY, Yellon DM, Davidson SM, Hausenloy DJ (2010) Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury. Circulation 121(18):2012–2022PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Chen L, Gong Q, Stice JP, Knowlton AA (2009) Mitochondrial OPA1, apoptosis, and heart failure. Cardiovasc Res 84(1):91–99PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Makino A, Scott BT, Dillmann WH (2010) Mitochondrial fragmentation and superoxide anion production in coronary endothelial cells from a mouse model of type 1 diabetes. Diabetologia 53(8):1783–1794PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Yu T, Sheu SS, Robotham JL, Yoon Y (2008) Mitochondrial fission mediates high glucose-induced cell death through elevated production of reactive oxygen species. Cardiovasc Res 79(2):341–351PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Huss JM, Kelly DP (2005) Mitochondrial energy metabolism in heart failure: a question of balance. J Clin Invest 115(3):547–555PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Hom JR, Quintanilla RA, Hoffman DL, de Mesy Bentley KL, Molkentin JD, Sheu SS, Porter GA Jr (2011) The permeability transition pore controls cardiac mitochondrial maturation and myocyte differentiation. Dev Cell 21(3):469–478PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Pennanen C, Parra V, Lopez-Crisosto C, Morales PE, Del Campo A, Gutierrez T, Rivera-Mejias P, Kuzmicic J, Chiong M, Zorzano A, Rothermel BA, Lavandero S (2014) Mitochondrial fission is required for cardiomyocyte hypertrophy mediated by a Ca2+-calcineurin signaling pathway. J Cell Sci 127(Pt 12):2659–2671PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Xu X, Duan S, Yi F, Ocampo A, Liu GH, Izpisua Belmonte JC (2013) Mitochondrial regulation in pluripotent stem cells. Cell Metab 18(3):325–332PubMedCrossRefPubMedCentralGoogle Scholar
  121. 121.
    Salabei JK, Hill BG (2013) Mitochondrial fission induced by platelet-derived growth factor regulates vascular smooth muscle cell bioenergetics and cell proliferation. Redox Biol 1:542–551PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Sharp WW, Fang YH, Han M, Zhang HJ, Hong Z, Banathy A, Morrow E, Ryan JJ, Archer SL (2014) Dynamin-related protein 1 (Drp1)-mediated diastolic dysfunction in myocardial ischemia-reperfusion injury: therapeutic benefits of Drp1 inhibition to reduce mitochondrial fission. FASEB J 28(1):316–326PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Chen Y, Liu Y, Dorn GW 2nd (2011) Mitochondrial fusion is essential for organelle function and cardiac homeostasis. Circ Res 109(12):1327–1331PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Papanicolaou KN, Khairallah RJ, Ngoh GA, Chikando A, Luptak I, O'Shea KM, Riley DD, Lugus JJ, Colucci WS, Lederer WJ, Stanley WC, Walsh K (2011) Mitofusin-2 maintains mitochondrial structure and contributes to stress-induced permeability transition in cardiac myocytes. Mol Cell Biol 31(6):1309–1328PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Papanicolaou KN, Ngoh GA, Dabkowski ER, O’Connell KA, Ribeiro RF Jr, Stanley WC, Walsh K (2012) Cardiomyocyte deletion of mitofusin-1 leads to mitochondrial fragmentation and improves tolerance to ROS-induced mitochondrial dysfunction and cell death. Am J Physiol Heart Circ Physiol 302(1):H167–H179PubMedCrossRefPubMedCentralGoogle Scholar
  126. 126.
    Piquereau J, Caffin F, Novotova M, Prola A, Garnier A, Mateo P, Fortin D, Huynhle H, Nicolas V, Alavi MV, Brenner C, Ventura-Clapier R, Veksler V, Joubert F (2012) Down-regulation of OPA1 alters mouse mitochondrial morphology, PTP function, and cardiac adaptation to pressure overload. Cardiovasc Res 94(3):408–417PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Olichon A, Baricault L, Gas N, Guillou E, Valette A, Belenguer P, Lenaers G (2003) Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J Biol Chem 278(10):7743–7746PubMedCrossRefPubMedCentralGoogle Scholar
  128. 128.
    Ihara S, Maeda-Takekoshi F, Takekoshi M, Yokoyama M, Sakuma S, Watanabe Y (1991) Evidence that the tyrosine kinase domain of a small fraction of epidermal growth factor receptor molecules is exposed on the outer surface of A431 cells. Cell Struct Funct 16(3):217–223PubMedCrossRefPubMedCentralGoogle Scholar
  129. 129.
    Gegg ME, Cooper JM, Chau KY, Rojo M, Schapira AH, Taanman JW (2010) Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy. Hum Mol Genet 19(24):4861–4870PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    de Brito OM, Scorrano L (2008) Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456(7222):605–610PubMedCrossRefGoogle Scholar
  131. 131.
    Chen KH, Guo X, Ma D, Guo Y, Li Q, Yang D, Li P, Qiu X, Wen S, Xiao RP, Tang J (2004) Dysregulation of HSG triggers vascular proliferative disorders. Nat Cell Biol 6(9):872–883PubMedCrossRefGoogle Scholar
  132. 132.
    Guo YH, Chen K, Gao W, Li Q, Chen L, Wang GS, Tang J (2007) Overexpression of Mitofusin 2 inhibited oxidized low-density lipoprotein induced vascular smooth muscle cell proliferation and reduced atherosclerotic lesion formation in rabbit. Biochem Biophys Res Commun 363(2):411–417PubMedCrossRefPubMedCentralGoogle Scholar
  133. 133.
    Guo X, Chen KH, Guo Y, Liao H, Tang J, Xiao RP (2007) Mitofusin 2 triggers vascular smooth muscle cell apoptosis via mitochondrial death pathway. Circ Res 101(11):1113–1122PubMedCrossRefPubMedCentralGoogle Scholar
  134. 134.
    Hall AR, Burke N, Dongworth RK, Hausenloy DJ (2014) Mitochondrial fusion and fission proteins: novel therapeutic targets for combating cardiovascular disease. Br J Pharmacol 171(8):1890–1906PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Klionsky DJ, Baehrecke EH, Brumell JH, Chu CT, Codogno P, Cuervo AM, Debnath J, Deretic V, Elazar Z, Eskelinen EL, Finkbeiner S, Fueyo-Margareto J, Gewirtz D, Jaattela M, Kroemer G, Levine B, Melia TJ, Mizushima N, Rubinsztein DC, Simonsen A, Thorburn A, Thumm M, Tooze SA (2011) A comprehensive glossary of autophagy-related molecules and processes (2nd edition). Autophagy 7(11):1273–1294PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Dai DF, Rabinovitch PS, Ungvari Z (2012) Mitochondria and cardiovascular aging. Circ Res 110(8):1109–1124PubMedCrossRefPubMedCentralGoogle Scholar
  137. 137.
    Twig G, Elorza A, Molina AJ, Mohamed H, Wikstrom JD, Walzer G, Stiles L, Haigh SE, Katz S, Las G, Alroy J, Wu M, Py BF, Yuan J, Deeney JT, Corkey BE, Shirihai OS (2008) Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 27(2):433–446PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Carreira RS, Lee Y, Ghochani M, Gustafsson AB, Gottlieb RA (2010) Cyclophilin D is required for mitochondrial removal by autophagy in cardiac cells. Autophagy 6(4):462–472PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Hirota Y, Kang D, Kanki T (2012) The physiological role of mitophagy: new insights into phosphorylation events. Int J Cell Biol 2012:354914PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Canto C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, Elliott PJ, Puigserver P, Auwerx J (2009) AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458(7241):1056–1060PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Karbowski M, Kurono C, Wozniak M, Ostrowski M, Teranishi M, Nishizawa Y, Usukura J, Soji T, Wakabayashi T (1999) Free radical-induced megamitochondria formation and apoptosis. Free Radic Biol Med 26(3–4):396–409PubMedCrossRefPubMedCentralGoogle Scholar
  142. 142.
    Terman A, Kurz T, Navratil M, Arriaga EA, Brunk UT (2010) Mitochondrial turnover and aging of long-lived postmitotic cells: the mitochondrial-lysosomal axis theory of aging. Antioxid Redox Signal 12(4):503–535PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Taneike M, Yamaguchi O, Nakai A, Hikoso S, Takeda T, Mizote I, Oka T, Tamai T, Oyabu J, Murakawa T, Nishida K, Shimizu T, Hori M, Komuro I, Takuji Shirasawa TS, Mizushima N, Otsu K (2010) Inhibition of autophagy in the heart induces age-related cardiomyopathy. Autophagy 6(5):600–606PubMedCrossRefPubMedCentralGoogle Scholar
  144. 144.
    Lesnefsky EJ, Moghaddas S, Tandler B, Kerner J, Hoppel CL (2001) Mitochondrial dysfunction in cardiac disease: ischemia–reperfusion, aging, and heart failure. J Mol Cell Cardiol 33(6):1065–1089PubMedCrossRefPubMedCentralGoogle Scholar
  145. 145.
    Matsui Y, Takagi H, Qu X, Abdellatif M, Sakoda H, Asano T, Levine B, Sadoshima J (2007) Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ Res 100(6):914–922PubMedCrossRefPubMedCentralGoogle Scholar
  146. 146.
    Hamacher-Brady A, Brady NR, Gottlieb RA (2006) Enhancing macroautophagy protects against ischemia/reperfusion injury in cardiac myocytes. J Biol Chem 281(40):29776–29787PubMedCrossRefPubMedCentralGoogle Scholar
  147. 147.
    Xie Z, Lau K, Eby B, Lozano P, He C, Pennington B, Li H, Rathi S, Dong Y, Tian R, Kem D, Zou MH (2011) Improvement of cardiac functions by chronic metformin treatment is associated with enhanced cardiac autophagy in diabetic OVE26 mice. Diabetes 60(6):1770–1778PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Akazawa H, Komazaki S, Shimomura H, Terasaki F, Zou Y, Takano H, Nagai T, Komuro I (2004) Diphtheria toxin-induced autophagic cardiomyocyte death plays a pathogenic role in mouse model of heart failure. J Biol Chem 279(39):41095–41103PubMedCrossRefPubMedCentralGoogle Scholar
  149. 149.
    Ungvari Z, Bailey-Downs L, Gautam T, Sosnowska D, Wang M, Monticone RE, Telljohann R, Pinto JT, de Cabo R, Sonntag WE, Lakatta EG, Csiszar A (2011) Age-associated vascular oxidative stress, Nrf2 dysfunction, and NF-{kappa}B activation in the nonhuman primate Macaca mulatta. J Gerontol A Biol Sci Med Sci 66(8):866–875PubMedCrossRefPubMedCentralGoogle Scholar
  150. 150.
    Ungvari Z, Csiszar A (2012) The emerging role of IGF-1 deficiency in cardiovascular aging: recent advances. J Gerontol A Biol Sci Med Sci 67(6):599–610PubMedCrossRefPubMedCentralGoogle Scholar
  151. 151.
    Sonntag WE, Csiszar A, deCabo R, Ferrucci L, Ungvari Z (2012) Diverse roles of growth hormone and insulin-like growth factor-1 in mammalian aging: progress and controversies. J Gerontol A Biol Sci Med Sci 67(6):587–598PubMedCrossRefPubMedCentralGoogle Scholar
  152. 152.
    Csiszar A, Labinskyy N, Perez V, Recchia FA, Podlutsky A, Mukhopadhyay P, Losonczy G, Pacher P, Austad SN, Bartke A, Ungvari Z (2008) Endothelial function and vascular oxidative stress in long-lived GH/IGF-deficient Ames dwarf mice. Am J Physiol Heart Circ Physiol 295(5):H1882–H1894PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Hao CN, Geng YJ, Li F, Yang T, Su DF, Duan JL, Li Y (2011) Insulin-like growth factor-1 receptor activation prevents hydrogen peroxide-induced oxidative stress, mitochondrial dysfunction and apoptosis. Apoptosis 16(11):1118–1127PubMedCrossRefPubMedCentralGoogle Scholar
  154. 154.
    Zhang D, Mott JL, Farrar P, Ryerse JS, Chang SW, Stevens M, Denniger G, Zassenhaus HP (2003) Mitochondrial DNA mutations activate the mitochondrial apoptotic pathway and cause dilated cardiomyopathy. Cardiovasc Res 57(1):147–157PubMedCrossRefPubMedCentralGoogle Scholar
  155. 155.
    Dai DF, Johnson SC, Villarin JJ, Chin MT, Nieves-Cintron M, Chen T, Marcinek DJ, Dorn GW 2nd, Kang YJ, Prolla TA, Santana LF, Rabinovitch PS (2011) Mitochondrial oxidative stress mediates angiotensin II-induced cardiac hypertrophy and Galphaq overexpression-induced heart failure. Circ Res 108(7):837–846PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Pepe M, Mamdani M, Zentilin L, Csiszar A, Qanud K, Zacchigna S, Ungvari Z, Puligadda U, Moimas S, Xu X, Edwards JG, Hintze TH, Giacca M, Recchia FA (2010) Intramyocardial VEGF-B167 gene delivery delays the progression towards congestive failure in dogs with pacing-induced dilated cardiomyopathy. Circ Res 106(12):1893–1903PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Doughan AK, Harrison DG, Dikalov SI (2008) Molecular mechanisms of angiotensin II-mediated mitochondrial dysfunction: linking mitochondrial oxidative damage and vascular endothelial dysfunction. Circ Res 102(4):488–496PubMedCrossRefPubMedCentralGoogle Scholar
  158. 158.
    Kimura S, Zhang GX, Nishiyama A, Shokoji T, Yao L, Fan YY, Rahman M, Abe Y (2005) Mitochondria-derived reactive oxygen species and vascular MAP kinases: comparison of angiotensin II and diazoxide. Hypertension 45(3):438–444PubMedCrossRefPubMedCentralGoogle Scholar
  159. 159.
    Davis RC, Hobbs FD, Lip GY (2000) ABC of heart failure. History and epidemiology. BMJ 320(7226):39–42PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Vasanthi HR, ShriShriMal N, Das DK (2012) Phytochemicals from plants to combat cardiovascular disease. Curr Med Chem 19(14):2242–2251PubMedCrossRefPubMedCentralGoogle Scholar
  161. 161.
    Kong Y, Trabucco SE, Zhang H (2014) Oxidative stress, mitochondrial dysfunction and the mitochondria theory of aging. Interdiscip Top Gerontol 39:86–107PubMedCrossRefPubMedCentralGoogle Scholar
  162. 162.
    Liu Z, Xu S, Huang X, Wang J, Gao S, Li H, Zhou C, Ye J, Chen S, Jin ZG, Liu P (2015) Cryptotanshinone, an orally bioactive herbal compound from Danshen, attenuates atherosclerosis in apolipoprotein E-deficient mice: role of lectin-like oxidized LDL receptor-1 (LOX-1). Br J Pharmacol 172(23):5661–5675PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Xu Y, Liu Q, Xu Y, Liu C, Wang X, He X, Zhu N, Liu J, Wu Y, Li Y, Li N, Feng T, Lai F, Zhang M, Hong B, Jiang JD, Si S (2014) Rutaecarpine suppresses atherosclerosis in ApoE-/- mice through upregulating ABCA1 and SR-BI within RCT. J Lipid Res 55(8):1634–1647PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Jia S, Hu C (2010) Pharmacological effects of rutaecarpine as a cardiovascular protective agent. Molecules 15(3):1873–1881PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Cimen I, Kocaturk B, Koyuncu S, Tufanli O, Onat UI, Yildirim AD, Apaydin O, Demirsoy S, Aykut ZG, Nguyen UT, Watkins SM, Hotamisligil GS, Erbay E (2016) Prevention of atherosclerosis by bioactive palmitoleate through suppression of organelle stress and inflammasome activation. Sci Transl Med 8(358):358ra126PubMedCrossRefPubMedCentralGoogle Scholar
  166. 166.
    Luo Y, Sun G, Dong X, Wang M, Qin M, Yu Y, Sun X (2015) Isorhamnetin attenuates atherosclerosis by inhibiting macrophage apoptosis via PI3K/AKT activation and HO-1 induction. PLoS One 10(3):e0120259PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Miura Y, Chiba T, Tomita I, Koizumi H, Miura S, Umegaki K, Hara Y, Ikeda M, Tomita T (2001) Tea catechins prevent the development of atherosclerosis in apoprotein E-deficient mice. J Nutr 131(1):27–32PubMedCrossRefPubMedCentralGoogle Scholar
  168. 168.
    Babu PV, Liu D (2008) Green tea catechins and cardiovascular health: an update. Curr Med Chem 15(18):1840–1850PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Punithavathi VR, Stanely Mainzen Prince P (2011) The cardioprotective effects of a combination of quercetin and alpha-tocopherol on isoproterenol-induced myocardial infarcted rats. J Biochem Mol Toxicol 25(1):28–40PubMedCrossRefPubMedCentralGoogle Scholar
  170. 170.
    Joshipura KJ, Ascherio A, Manson JE, Stampfer MJ, Rimm EB, Speizer FE, Hennekens CH, Spiegelman D, Willett WC (1999) Fruit and vegetable intake in relation to risk of ischemic stroke. JAMA 282(13):1233–1239PubMedCrossRefPubMedCentralGoogle Scholar
  171. 171.
    Gorinstein S, Caspi A, Libman I, Lerner HT, Huang D, Leontowicz H, Leontowicz M, Tashma Z, Katrich E, Feng S, Trakhtenberg S (2006) Red grapefruit positively influences serum triglyceride level in patients suffering from coronary atherosclerosis: studies in vitro and in humans. J Agric Food Chem 54(5):1887–1892PubMedCrossRefPubMedCentralGoogle Scholar
  172. 172.
    Rangel-Huerta OD, Pastor-Villaescusa B, Aguilera CM, Gil A (2015) A systematic review of the efficacy of bioactive compounds in cardiovascular disease: phenolic compounds. Nutrients 7(7):5177–5216PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Reis JF, Monteiro VV, de Souza Gomes R, do Carmo MM, da Costa GV, Ribera PC, Monteiro MC (2016) Action mechanism and cardiovascular effect of anthocyanins: a systematic review of animal and human studies. J Transl Med 14(1):315PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Wallace TC (2011) Anthocyanins in Cardiovascular Disease. Adv Nutr 2(1):1–7PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Wallace TC, Slavin M, Frankenfeld CL (2016) Systematic review of anthocyanins and markers of cardiovascular disease. Nutrients 8(1)PubMedCentralCrossRefGoogle Scholar
  176. 176.
    Scolaro B, Soo Jin Kim H, de Castro IA (2018) Bioactive compounds as an alternative for drug co-therapy: overcoming challenges in cardiovascular disease prevention. Crit Rev Food Sci Nutr 58(6):958–971PubMedCrossRefPubMedCentralGoogle Scholar
  177. 177.
    Bonnefont-Rousselot D (2016) Resveratrol and cardiovascular diseases. Nutrients 8(5)PubMedCentralCrossRefGoogle Scholar
  178. 178.
    Vidavalur R, Otani H, Singal PK, Maulik N (2006) Significance of wine and resveratrol in cardiovascular disease: French paradox revisited. Exp Clin Cardiol 11(3):217–225PubMedPubMedCentralGoogle Scholar
  179. 179.
    Qin M, Luo Y, Meng XB, Wang M, Wang HW, Song SY, Ye JX, Pan RL, Yao F, Wu P, Sun GB, Sun XB (2015) Myricitrin attenuates endothelial cell apoptosis to prevent atherosclerosis: An insight into PI3K/Akt activation and STAT3 signaling pathways. Vasc Pharmacol 70:23–34CrossRefGoogle Scholar
  180. 180.
    Honarbakhsh S, Schachter M (2009) Vitamins and cardiovascular disease. Br J Nutr 101(8):1113–1131PubMedCrossRefPubMedCentralGoogle Scholar
  181. 181.
    Al-Yahya MA, Mothana RA, Al-Said MS, El-Tahir KE, Al-Sohaibani M, Rafatullah S (2013) Citrus medica “Otroj”: attenuates oxidative stress and cardiac dysrhythmia in isoproterenol-induced cardiomyopathy in rats. Nutrients 5(11):4269–4283PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Sharmistha Chatterjee
    • 1
  • Uday Hossain
    • 1
  • Parames C. Sil
    • 1
    Email author
  1. 1.Division of Molecular MedicineBose InstituteKolkataIndia

Personalised recommendations