, Volume 24, Issue 1, pp 1–10 | Cite as

Atherosclerotic cardiovascular disease: a review of initiators and protective factors

  • Mohammed S. Ellulu
  • Ismail Patimah
  • Huzwah Khaza’ai
  • Asmah Rahmat
  • Yehia Abed
  • Faisal Ali


Atherosclerotic cardiovascular disease (CVD) is a collective term comprising of a group of disorders of the heart and blood vessels. These diseases are the largest cause of morbidity and premature death worldwide. Coronary heart disease and cerebrovascular disease (stroke) are the most frequently occurring diseases. The two major initiators involved in the development of atherosclerotic CVD are vascular production of reactive oxygen species (ROS) and lipid oxidation. In atherosclerosis development, ROS is associated with rapid loss of anti-inflammatory and anti-atherogenic activities of the endothelium-derived nitric oxide (NO·) resulting in endothelial dysfunction. In part involving activation of the transcription factor NF-κB, ROS have been involved in signaling cascades leading to vascular pro-inflammatory and pro-thrombotic gene expression. ROS is also a potent activator of matrix metalloproteinases (MMPs), which indicate plaque destabilization and rupture. The second initiator involved in atherosclerotic CVD is the oxidation of low-density lipoproteins (LDL). Oxidation of LDL in vessel wall leads to an inflammatory cascade that activates atherogenic pathway leading to foam cell formation. The accumulation of foam cells leads to fatty streak formation, which is the earliest visible atherosclerotic lesion. In contrast, the cardiac sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) and hepatic apolipoprotein E (apoE) expression can improve cardiovascular function. SERCA2a regulates the cardiac contractile function by lowering cytoplasmic calcium levels during relaxation, and affecting NO· action in vascular cells, while apoE is a critical ligand in the plasma clearance of triglyceride- and cholesterol-rich lipoproteins.


Reactive oxygen species, ROS NAD(P)H oxidase Endothelial dysfunction Lipoprotein oxidation Inflammation Thrombosis Matrix metalloproteinases SERCA2a Hepatic apoE 


Compliance with ethical standards

Conflict of interest

The authors declare that there is no conflict of interest with respect to this work.


  1. Agha A, Schlüter H, König S, Biel K, Tepel M, Zidek W (1992) A novel platelet-derived renal vasoconstrictor agent in normotensives and essential hypertensives. J Vasc Res 29(3):281–289CrossRefPubMedGoogle Scholar
  2. Arai M, Matsui H, Periasamy M (1994) Sarcoplasmic reticulum gene expression in cardiac hypertrophy and heart failure. Circ Res 74(4):555–564CrossRefPubMedGoogle Scholar
  3. Baker AH, Edwards DR, Murphy G (2002) Metalloproteinase inhibitors: biological actions and therapeutic opportunities. J Cell Sci 115(Pt 19):3719–3727CrossRefPubMedGoogle Scholar
  4. Borén J, Olin K, Lee I, Chait A, Wight TN, Innerarity TL (1998) Identification of the principal proteoglycan-binding site in LDL. A single-point mutation in apo-B100 severely affects proteoglycan interaction without affecting LDL receptor binding. J Clin Invest 101(12):2658–2664PubMedCentralCrossRefPubMedGoogle Scholar
  5. Bourassa MG, Tardif JC (eds) (2006) Antioxidants and cardiovascular disease, 2nd edn. Springer Science & Business Media. ISBN: 978-0387-29552-7Google Scholar
  6. Camejo G, Fager G, Rosengren B, Hurt-Camejo E, Bondjers G (1993) Binding of low density lipoproteins by proteoglycans synthesized by proliferating and quiescent human arterial smooth muscle cells. J Biol Chem 268(19):14131–14137PubMedGoogle Scholar
  7. Collins T, Cybulsky MI (2001) NF-κB: pivotal mediator or innocent bystander in atherogenesis? J Clin Invest 107(3):255–264PubMedCentralCrossRefPubMedGoogle Scholar
  8. Cybulsky MI, Iiyama K, Li H, Zhu S, Chen M, Iiyama M et al (2001) A major role for VCAM-1, but not ICAM-1, in early atherosclerosis. J Clin Invest 107(10):1255–1262PubMedCentralCrossRefPubMedGoogle Scholar
  9. Davies CH, Davia K, Bennett JG, Pepper JR, Poole-Wilson PA, Harding SE (1995) Reduced contraction and altered frequency response of isolated ventricular myocytes from patients with heart failure. Circulation 92(9):2540–2549CrossRefPubMedGoogle Scholar
  10. Ferrari P, Micheletti R, Valentini G, Bianchi G (2007) Targeting SERCA2a as an innovative approach to the therapy of congestive heart failure. Med Hypotheses 68(5):1120–1125CrossRefPubMedGoogle Scholar
  11. Finkel T, Holbrook NJ (2000) Oxidants, oxidative stress and the biology of ageing. Nature 408(6809):239–247CrossRefPubMedGoogle Scholar
  12. Flood C, Gustafsson M, Richardson PE, Harvey SC, Segrest JP, Borén J (2002) Identification of the proteoglycan binding site in apolipoprotein B48. J Biol Chem 277(35):32228–32233CrossRefPubMedGoogle Scholar
  13. 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 Invest 94(6):2493–2503PubMedCentralCrossRefPubMedGoogle Scholar
  14. Gotto AM Jr, Farmer JA (1988) Risk factors for coronary artery disease. In: Braunwald E (ed) Heart disease: a textbook of cardiovascular medicine. Saunders, Philadelphia, pp 1153–1190Google Scholar
  15. Gotto AM Jr, Grundy SM (1999) Lowering LDL cholesterol: questions from recent meta-analyses and subset analyses of clinical trial data. Issues from the Interdisciplinary Council on Reducing the Risk for Coronary Heart Disease, ninth Council meeting. Circulation 99:E1–E7CrossRefPubMedGoogle Scholar
  16. Grote K, Flach I, Luchtefeld M, Akin E, Holland SM, Drexler H et al (2003) Mechanical stretch enhances mRNA expression and proenzyme release of matrix metalloproteinase-2 (MMP-2) via NAD (P) H oxidase–derived reactive oxygen species. Circ Res 92(11):e80–e86CrossRefPubMedGoogle Scholar
  17. Hakim J (1993) Reactive oxygen species and inflammation. C R Seances Soc Biol Fil 187(3):286–295PubMedGoogle Scholar
  18. Hasenfuss G, Reinecke H, Studer R, Meyer M, Pieske B, Holtz J et al (1994) Relation between myocardial function and expression of sarcoplasmic reticulum Ca2+-ATPase in failing and nonfailing human myocardium. Circ Res 75(3):434–442CrossRefPubMedGoogle Scholar
  19. Higashi Y, Noma K, Yoshizumi M, Kihara Y (2009) Endothelial function and oxidative stress in cardiovascular diseases. Circ J 73(3):411–418CrossRefPubMedGoogle Scholar
  20. Hink U, Li H, Mollnau H, Oelze M, Matheis E, Hartmann M et al (2001) Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res 88(2):e14–e22CrossRefPubMedGoogle Scholar
  21. Krötz F, Sohn HY, Gloe T, Zahler S, Riexinger T, Schiele TM et al (2002) NAD(P)H-oxidase-dependent platelet superoxide anion release increases platelet recruitment. Blood 100:917–924CrossRefPubMedGoogle Scholar
  22. Krötz F, Sohn HY, Pohl U (2004) Reactive oxygen species players in the platelet game. Arterioscler Thromb Vasc Biol 24(11):1988–1996CrossRefPubMedGoogle Scholar
  23. Kuipers F, Jong MC, Lin Y, Eck MV, Havinga R, Bloks V et al (1997) Impaired secretion of very low density lipoprotein-triglycerides by apolipoprotein E-deficient mouse hepatocytes. J Clin Invest 100(11):2915–2922PubMedCentralCrossRefPubMedGoogle Scholar
  24. Lakshmi SV, Padmaja G, Kuppusamy P, Kutala VK (2009) Oxidative stress in cardiovascular disease. Indian J Biochem Biophys 46:421–440PubMedGoogle Scholar
  25. Libby P (2012) Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol 32(9):2045–2051. doi: 10.1161/ATVBAHA.108.179705 PubMedCentralCrossRefPubMedGoogle Scholar
  26. Libby P, Ridker PM, Maseri A (2002) Inflammation and atherosclerosis. Circulation 105(9):1135–1143CrossRefPubMedGoogle Scholar
  27. Loscalzo J (2003) Oxidant stress: a key determinant of atherothrombosis. Biochem Soc Trans 31(Pt 5):1059–1061CrossRefPubMedGoogle Scholar
  28. Lüscher TF (1990) Imbalance of endothelium-derived relaxing and contracting factors a new concept in hypertension? Am J Hypertens 3(4):317–330CrossRefPubMedGoogle Scholar
  29. Mahley RW, Huang Y (1999) Apolipoprotein E: from atherosclerosis to Alzheimer’s disease and beyond. Curr Opin Lipidol 10(3):207–217CrossRefPubMedGoogle Scholar
  30. Mahley RW, Rall SC Jr (2000) Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet 1(1):507–537CrossRefPubMedGoogle Scholar
  31. Mahley RW, Weisgraber KH, Huang Y (2009) Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer’s disease to AIDS. J Lipid Res 50(Suppl):S183–S188. doi: 10.1194/jlr.R800069-JLR200
  32. Massova I, Kotra LP, Fridman R, Mobashery S (1998) Matrix metalloproteinases: structures, evolution, and diversification. FASEB J 12(12):1075–1095PubMedGoogle Scholar
  33. Maugeais C, Tietge UJ, Tsukamoto K, Glick JM, Rader DJ (2000) Hepatic apolipoprotein E expression promotes very low density lipoprotein-apolipoprotein B production in vivo in mice. J Lipid Res 41(10):1673–1679PubMedGoogle Scholar
  34. Morrow JD, Frei B, Longmire AW, Gaziano JM, Lynch SM, Shyr Y et al (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):1198–1203CrossRefPubMedGoogle Scholar
  35. Nakayama H, Otsu K, Yamaguchi O, Nishida K, Date MO, Hongo K et al (2003) Cardiac-specific overexpression of a high Ca2+ affinity mutant of SERCA2a attenuates in vivo pressure overload cardiac hypertrophy. FASEB J 17(1):61–63PubMedGoogle Scholar
  36. Nievelstein PF, Fogelman AM, Mottino G, Frank JS (1991) Lipid accumulation in rabbit aortic intima 2 hours after bolus infusion of low density lipoprotein. A deep-etch and immunolocalization study of ultrarapidly frozen tissue. Arterioscler Thromb 11(6):1795–1805CrossRefPubMedGoogle Scholar
  37. Patruno A, Pesce M, Marrone A, Speranza L, Grilli A, De Lutiis MA et al (2012) Activity of matrix metallo proteinases (MMPs) and the tissue inhibitor of MMP (TIMP)-1 in electromagnetic field-exposed THP-1 cells. J Cell Physiol 227(6):2767–2774. doi: 10.1002/jcp.23024 CrossRefPubMedGoogle Scholar
  38. Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren M et al (2012) European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J 33(13):1635–1701. doi: 10.1093/eurheartj/ehs092 CrossRefPubMedGoogle Scholar
  39. Pratico D, Pasin M, Barry OP, Ghiselli A, Sabatino G, Iuliano L et al (1999) Iron-dependent human platelet activation and hydroxyl radical formation: involvement of protein kinase C. Circulation 99:3118–3124CrossRefPubMedGoogle Scholar
  40. Proctor SD, Vine DF, Mamo JC (2002) Arterial retention of apolipoprotein B48-and B100-containing lipoproteins in atherogenesis. Curr Opin Lipidol 13(5):461–470CrossRefPubMedGoogle Scholar
  41. Qian H, Neplioueva V, Shetty GA, Channon KM, George SE (1999) Nitric oxide synthase gene therapy rapidly reduces adhesion molecule expression and inflammatory cell infiltration in carotid arteries of cholesterol-fed rabbits. Circulation 99(23):2979–2982CrossRefPubMedGoogle Scholar
  42. Radomski MW, Palmer RM, Moncada S (1987) Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium. Lancet 2:1057–1105CrossRefPubMedGoogle Scholar
  43. Rajagopalan S, Meng XP, Ramasamy S, Harrison DG, Galis ZS (1996) Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro. Implications for atherosclerotic plaque stability. J Clin Invest 98(11):2572–2579PubMedCentralCrossRefPubMedGoogle Scholar
  44. Rao GN, Berk BC (1992) Active oxygen species stimulate vascular smooth muscle cell growth and proto-oncogene expression. Circ Res 70(3):593–599CrossRefPubMedGoogle Scholar
  45. Schwedhelm E, Bartling A, Lenzen H, Tsikas D, Maas R, Brümmer J et al (2004) Urinary 8-iso-prostaglandin F2α as a risk marker in patients with coronary heart disease a matched case-control study. Circulation 109(7):843–848CrossRefPubMedGoogle Scholar
  46. Simionescu M, Simionescu N (1993) Proatherosclerotic events: pathobiochemical changes occurring in the arterial wall before monocyte migration. FASEB J 7(14):1359–1366PubMedGoogle Scholar
  47. Sorescu D, Weiss D, Lassègue B, Clempus RE, Szöcs K, Sorescu GP et al (2002) Superoxide production and expression of nox family proteins in human atherosclerosis. Circulation 105(12):1429–1435CrossRefPubMedGoogle Scholar
  48. Sottero B, Gargiulo S, Russo I, Barale C, Poli G, Cavalot F (2015) Postprandial dysmetabolism and oxidative stress in type 2 diabetes: pathogenetic mechanisms and therapeutic strategies. Med Res Rev 35(5):968–1031. doi: 10.1002/med.21349 CrossRefPubMedGoogle Scholar
  49. Steinberg D (2002) Atherogenesis in perspective: hypercholesterolemia and inflammation as partners in crime. Nat Med 8(11):1211–1217CrossRefPubMedGoogle Scholar
  50. Steinbrecher U, Parthasarathy S, Leake DS, Witztum JL, Steinberg D (1984) Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. Proc Natl Acad Sci 81(12):3883–3887PubMedCentralCrossRefPubMedGoogle Scholar
  51. Stocker R, Keaney JF (2004) Role of oxidative modifications in atherosclerosis. Physiol Rev 84(4):1381–1478CrossRefPubMedGoogle Scholar
  52. Sugamura K, Keaney JF (2011) Reactive oxygen species in cardiovascular disease. Free Radic Biol Med 51(5):978–992. doi: 10.1016/j.freeradbiomed.2011.05.004 PubMedCentralCrossRefPubMedGoogle Scholar
  53. Taleb A, Witztum JL, Tsimikas S (2011) Oxidized phospholipids on apoB-100-containing lipoproteins: a biomarker predicting cardiovascular disease and cardiovascular events. Biomark Med 5(5):673–694. doi: 10.2217/bmm.11.60 PubMedCentralCrossRefPubMedGoogle Scholar
  54. Tong X, Evangelista A, Cohen RA (2010) Targeting the redox regulation of SERCA in vascular physiology and disease. Curr Opin Pharmacol 10(2):133–138. doi: 10.1016/j.coph.2009.11.008 PubMedCentralCrossRefPubMedGoogle Scholar
  55. Trogdon JG, Finkelstein EA, Nwaise IA, Tangka FK, Orenstein D (2007) The economic burden of chronic cardiovascular disease for major insurers. Health Promot Pract 8(3):234–242CrossRefPubMedGoogle Scholar
  56. Turpaev KT (2002) Reactive oxygen species and regulation of gene expression. Biochemistry (Mosc) 67(3):281–292CrossRefGoogle Scholar
  57. Véniant MM, Pierotti V, Newland D, Cham CM, Sanan DA, Walzem RL et al (1997) Susceptibility to atherosclerosis in mice expressing exclusively apolipoprotein B48 or apolipoprotein B100. J Clin Invest 100(1):180–188PubMedCentralCrossRefPubMedGoogle Scholar
  58. Watanabe N, Ikeda U (2004) Matrix metalloproteinases and atherosclerosis. Curr Atheroscler Rep 6(2):112–120CrossRefPubMedGoogle Scholar
  59. Zalba G, San José G, Moreno MU, Fortuño MA, Fortuño A, Beaumont FJ et al (2001) Oxidative stress in arterial hypertension role of NAD(P)H oxidase. Hypertension 38(6):1395–1399CrossRefPubMedGoogle Scholar
  60. Zheng JS, Yang XQ, Lookingland KJ, Fink GD, Hesslinger C, Kapatos G et al (2003) Gene transfer of human guanosine 5′-triphosphate cyclohydrolase I restores vascular tetrahydrobiopterin level and endothelial function in low renin hypertension. Circulation 108(10):1238–1245CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing 2016

Authors and Affiliations

  1. 1.Department of Nutrition and Dietetics, Faculty of Medicine and Health SciencesUniversiti Putra Malaysia (UPM)SerdangMalaysia
  2. 2.Department of Biomedical Science, Faculty of Medicine and Health SciencesUniversiti Putra Malaysia (UPM)SerdangMalaysia
  3. 3.Faculty of Public HealthAl Quds University of GazaGazaPalestine

Personalised recommendations