Pathological Mechanism of Atherosclerosis


  • Muhammad Naeem Institute of Research and Information Mirpur, Azad Jammu and Kashmir
  • Irum Naureen Assistant Professor, Minhaj University Lahore
  • Aisha Saleem M. Phil Researcher, Minhaj University Lahore
  • Rabia Yousaf M. Phil Researcher, Minhaj University Lahore
  • Shafa Fatima M. Phil Researcher, Minhaj University Lahore
  • Memoona Saher M. Phil Researcher, Minhaj University Lahore
  • Iza Tahreem M. Phil Researcher, Minhaj University Lahore
  • Sehrish Rauf M. Phil Researcher, Minhaj University Lahore


Endothelial dysfunction, ROS, LDL, oxLDL, Macrophages, Foam cells, Plaque, NOS, hypercholesterolemia, microRNAs (miRNAs), proprotein convertase subtilisin/kexin type 9 (PCSK9) gene, telomere length (LTL)


Atherosclerosis is a multifactorial, smoldering, focal (intima of bifurcated blood arteries), chronic, progressive asymptotically, immune-inflammatory, disorder driven by lipid imbalance, in the large to medium sized (upto3mm external diameter) arteries with many cardiovascular clinical manifestations. Atherosclerosis developmentinvolves many cells, organs and even disturbed blood flow. The progression of atherosclerotic disease depends on the presence, degree, and persistence of risk factors like high-fat diet, smoking, hypertension, history of heart diseases, or diabetes. Endothelial dysfunction, ROS, accumulation of LDL, recruitment of Monocytes and T cells, differentiation of monocytes into macrophages and foam cells, formation of plaque and rupturing of plaque are key steps behind the clinical manifestation of atherosclerosis in cardiovascular diseases. This article describes the pathogenesis of atherosclerosis, possibility of therapeutically targeting mechanism and interventions which can be helpful to reverse or slower the atherosclerosis. 


Mendis S, Puska P, and Norrving B: 2011. ‘‘Global Atlas on Cardiovascular Disease Prevention and Control. Editors’’. World Health Organization, Geneva 2011.

Mozaffarian D, Benjamin E,Robert, W. Neumar, Graham Nichol, Latha Palaniappan, Go A : 2016. ‘‘Heart disease and stroke statistics-2016 update; a report from the American Heart Association’’, Circulation 2016; 38:133-e360. 10.1161/CIR.0000000000000350

Causes of death: 2008. ‘‘World Health Organization, Geneva,’’ global_burden_disease/ cod_2008_sources_methods.pdf.

World Health Organization and World Economic Forum, From Burden to "Best Buys": ‘‘Reducing the Economic Impact of Non-Communicable Diseases in Low- and Middle-Income Countries’’. Geneva: World Economic Forum 2011.

MD, Ashen. R.S.Blumenthal, (2005). ‘‘Low HDL Cholesterol Levels New England J of Medicine’’, 353:1252–1260.

Kornelia Kotseva , David Wood, Guy De Backer, Dirk De Bacquer, Kalevi Pyörälä, and Zeljko Reiner: 2010. Euroaspire Study Group. Euroaspire III. ‘‘Management of cardiovascular risk factors in asymptomatic high-risk patients in general practice: Cross-sectional survey in 12 European countries’’. European Journal of Cardiovascular Prevention and Rehabilitation, 17: 530–540

Mendis, samual. Jamal, S. Rana, Christopher Prendergast, Henry McGill, J Jeffery Carr , and Kiang Liu : (2005). ‘‘Report for the Pathobiological Determinants of Atherosclerosis in Youth (PBDAY) Research Group: Atherosclerosis in children and young adults: An overview of the World Health Organization and International Society and Federation of Cardiology Study on Pathobiological Determinants of Atherosclerosis in Youth Study 1985– 1995’’, Prevention and Control 2005; 1:3–15.

Clara K Chow , Koon K Teo, Sumathy Rangarajan, Shofiqul Islam, Rajeev Gupta, and Alvaro Avezum: 2013. Prevalence, Awareness, Treatment, and Control of Hypertension in Rural and Urban Communities in High, Middle, and Low-Income Countries, JAMA, 310:959–968. doi:10.1001/jama.2013.184182

Peter, Jennrich. (2013). ‘‘The Influence of Arsenic, Lead, and Mercury on the Development of Cardiovascular Diseases’’, International Scholarly Research: 23: 470-476

Goodarz, Danaei. Mariel, M. Finucane, John, K. Lin, Gitanjali, M. Singh, Christopher. J. Paciorek, and Melanie, J. Cowan. (2011). ‘‘National, regional, and global trends in systolic blood pressure since 1980: systematic analysis of health examination surveys and epidemiological studies with 786 country-years and 5·4 million participants’’, 377:568-577, ISSN 0140-6736,

Christopher, K. Steinberg, D. Yokode, M. Kita, T. Kawai, C. and J. L. Witztum. (2001). ‘‘Atherosclerosis’’: The Road Ahead, 104: 503–516

Kobiyama,. K and Ley, K. (2018). ‘‘Atherosclerosis’’, Circ Res; 123: 1118-1120,

Brown, J.D. Lin, C.Y. Duan, Q. Griffin, G. Federation, A. Paranal, RM. (2014). ‘‘NF-kappaB directs dynamic super enhancer formation in inflammation and atherogenesis’’. Mol cell 2014; 56: 219–231

Russell, L. Holman, Henry, C. McGill, Jr. Jack, P. Strong, and jack, c. Geer. (1958). ‘‘The natural history of atherosclerosis the early aortic lesions as seen in New Orleans in the middle of the 20th century’’, The American Journal of Pathology ; 34:209-35

Napoli, C. D. Armiento, F.P. Mancini, F.P. Postiglione, A. Witztum, J.L. Palumbo, and Palinski, W. (1997). ‘‘Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions’’, J Clin, Invest. 100: 2680–2690

Sauer, H. & Wartenberg, M. (2008). ‘‘Circulating isoprostanes: Gate keepers in the route from oxidative stress to vascular dysfunction’’ Circulation Research, 2008; 103:907–909, doi:10.1161/CIRCRESAHA.108.187278

Kinlay S, Libby P. Ganz P. (2001) ‘‘Endothelial function and coronary artery disease’’. CurrOpinLipidol. 12:383–389

Li, H. Cybulsky, M.I. Gimbrone, M.A. Jr. Libby, p. Watanabe, T. Fan, J. et al. (1993) ‘‘An atherogenic diet rapidly induces VCAM-1, a cytokine regulatable mononuclear leukocyte adhesion molecule, in rabbit endothelium’’. ArteriosclerThromb. 13: 197–204

Griendling, K.K. Ushio-Fukai, M. Lassegue, B.R W Alexander, Touyz, R.M. Berry, al. (1997) ‘‘Angiotensin II signaling in vascular smooth muscle: new concepts’’. Hypertension 1997;29: 366–373

Martinez-Gonzalez, J. Raposo, B. Rodriguez, C.L. Badimon, Sánchez-Pascuala, R. Hernández ,G. et al..(2001) ‘‘3-Hydroxy-3- methylglutaryl coenzyme A reductase inhibition prevents endothelial NO synthase downregulation by atherogenic levels of native LDLs: balance between transcriptional and posttranscriptional regulation’’. ArteriosclerThrombVascBiol 5:804–809.

Heitzer, T. Schlinzig, T. Krohn, K. T. Meinertz, T. Münzel,Rudolph, V. (2001). ‘‘Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease’’ Circulation; 104:2673–2678.

R. Ross. (1986). “The pathogenesis of atherosclerosis an update,” The New England Journal of Medicine, 314: 488–500,

M. Khazaei, F.Moien-afshari, and I. Laher (2008). “Vascular endothelial function in health and diseases,” Pathophysiology, 15: 49–67,

Schwenke, D.C. and Carew, T.E. (1989). ‘‘Initiation of atherosclerotic lesions in cholesterol-fed rabbits II: Selective retention of LDL vs. sclective increases in LDL permeability in susceptible sites of arteries’’ Arreriosclerosis; 9: 908

Cerrity, R.G. Richardson, M. Somer, J.B. Bell, F.P. and Schwartz, C. J. (1977). Endothelial cell morphology in areas of in vivo Evans Blue uptake in the young pig aorta: Ultrastructure of the intima in areas of differing permeability to proteins. Am J Puthol,89: 313

Cooke, J.P. (2000). ‘‘Does ADMA cause endothelial dysfunction’’? ArteriosclerThrombVascBi;20:2032–2037

Lu¨scher, T.F. and Barton, M. (1997). Biology of the endothelium, ClinCardiol; 20:3-10.

JL. Goldstein and M.S. Brown (2015). “A century of cholesterol and coronaries: from plaques to genes to statins’’ 2015; 16:161–172,

AC Santos, M.J.N.N. Alves, M.U.P.B. Rondon, A.C.P. Barretto, H.R Middlekauff, and C.E. Negrão (2005).“Sympathetic activation restrains endothelium-mediated muscle vasodilatation in heart failure patients,” American Journal of Physiology-Heart and Circulatory Physiology, 289: H593–H599,

D. Harrison, K.K. Griendling, U.Landmesser, B. Hornig, and H. Drexler. (2003). “Role of oxidative stress in atherosclerosis,” The American Journal of Cardiology 2003; 91: 7–11

C.J Binder, N. Papac-Milicevic, and J. L Witztum (2016) “Innate sensing of oxidation-specific epitopes in health and disease,” Nature Reviews Immunology, 16: 485–497,

CP. Sparrow, S. Parthasarathy, and D. Steinberg: 1988. “Enzymatic modification of low density lipoprotein by purified lipoxygenase plus phospholipase A2 mimics cell-mediated oxidative modification,” Journal of Lipid Research, 29: 745–753,

H. Esterbauer, J. Gebicki, H. Puhl, and G. Jürgens (1992) “The role of lipid peroxidation and antioxidants in oxidative modification of LDL,” Free Radical Biology & Medicine, 13:341–390

Jimmy, F.P. Berbée , Isabel, M.Mol, Ginger, L. Milne, Erik. Pollock, Geerte, Hoeke, and Dieter, Lütjohann (2017). “Deuterium-reinforced polyunsaturated fatty acids protect against atherosclerosis by lowering lipid peroxidation and hypercholesterolemia,” Atherosclerosis, 264:100–107

L. Cominacini, A. Rigoni, A.F. Pasini, U. Garbin, A Davoli, M. Campagnola (2001). “The binding of oxidized low density lipoprotein (ox-LDL) to ox-LDL receptor-1 reduces the intracellular concentration of nitric oxide in endothelial cells through an increased production of superoxide,” The Journal of Biological Chemistry, 276: 13750–13755

Christopher, K. Steinberg, D. Yokode, M. Kita, T. Kawai, C. and J. L Witztum. (2001). Atherosclerosis: The Road Ahead Cell, 104:503–516

CDA. Goonasekera (2009). “Vascular Endothelial Cell Activation Associated with Increased Plasma Asymmetric Dimethyl Arginine in Children and Young Adults with Hypertension: A Basis for Atheroma. Blood Pressure, 9:16–21

L. Cominacini, A. Rigoni, AF. Pasini A. Rigoni, AF. Pasini, U Garbin, A Davoli, M Campagnola: 2001. “The binding of oxidized low density lipoprotein (ox-LDL) to ox-LDL receptor-1 reduces the intracellular concentration of nitric oxide in endothelial cells through an increased production of superoxide,” The Journal of Biological Chemistry, 276:13750–13755

Springer, T.A. (1994). ‘‘Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm, Cell’’. 76:301–314.

Zernecke, A. Shagdarsuren, E. and Weber, C. (2008). ‘Chemokines in atherosclerosis: an update’’. ArteriosclerThromb Vasc Biol, 28: 1897–1908.

Hazen, S. L. (2008). ‘‘Oxidized phospholipids as endogenous pattern recognition ligands in innate immunity’’ Journal of Biological Chemistry, 283: 15527–15531.

Libby, P. (2002) ‘‘Inflammation in atherosclerosis; Nature’’, 420:868–874. doi:10.1038/nature01323

Orecchioni, Marco. Yanal,Ghosheh. Akula Bala, Pramod. Klaus Ley,Checkouri, E. and Blanchard V. (2019). ‘‘Macrophage Polarization: Different Gene Signatures in M1(LPS+) vs. Classically and M2(LPS–) vs. Alternatively Activated Macrophages’’ Frontiers in Immunology, 10:84-89

NiuXiaoling, Grant, S. Schulert,Ragni, E. Papait, A. Perucca, Orfei C. and Silini, A.R. (2019). ‘‘Functional Regulation of Macrophage Phenotypes by MicroRNAs in Inflammatory Arthritis’’ Frontiers in Immunology, 10: 17-22

Dereck Salisbury,U.l.f. Bronas,Leonarduzzi, G. Gamba, P. Gargiulo, S. Biasi, F. (2014). ‘‘Inflammation and Immune System Contribution to the Etiology of Atherosclerosis’’ Nursing Research, September/October; 63: 375–385. DOI: 10.1097/NNR.0000000000000053

Brown, M.S and Goldstein, JL. (1986) ‘‘A receptor-mediated pathway for cholesterol homeostasis’’ Science; 232: 34–47.

Rajendra, K. Tangirala, Eric D. Bischoff Sean, Joseph, and Brandee, L. (2002). ‘‘Identification of macrophage liver X receptors as inhibitors of atherosclerosis’’ Proceedings of the National Academy of Sciences United States of America, 99: 11896–11901.

Collin, S.P. Carleena, O. Joshua, A.D. Gordon, A.F. (2019). ‘‘Pathways of smooth muscle foam cell formation in atherosclerosis’’ CurrOpinLipidol ; 30:117e124

Fu-Ju, Tian. Li-Na, An Guo-Kun, Wang , Jia-Qi Zhu , Qing Li . Ying-Ying Zhang. (2014). ‘‘Elevated microRNA-155 promotes foam cell formation by targeting HBP1 inatherogenesis’’ Cardiovasc Res; 103: 100-110.

Alberto. Canfrán-Duque, Noemi Rotllan , Xinbo. Zhang , Marta. Fernández-Fuertes , Cristina. Ramírez-Hidalgos and Elisa, Araldi . (2017). Macrophage deficiency of miR-21 promotes apoptosis, plaque necrosis, and vascular inflammation during atherogenesis. EMBO Mol Med, 9:1244-1262.

Mei-Hua, Bao. Jian-Ming Li , Qi-Liang, Zhou. Guang-Yi Li , Jie Zeng , Juan Zhao. (2016) ‘‘Effects of miR-590 on oxLDL-induced endothelial cell apoptosis: roles of p53 and NF-Kb’’. Mol Med Rep, 13:867-873.

Hesslcr, J.R. Morel, D.W. Lewis, L.J. and Chiaolin, GM. (1983). ‘Lipoprotein oxid;ition and lipoprotein-induced cytotoxicity’’ . Arteriosclerosis; 3:215

Fielding, P.E. Fielding, C.J. Have1, R.J. Kane, J.P. and Tun, P. (1983). ‘‘Cholesterol net transport, esterification, and transfer in human hyperlipidemic plasma.’’ J Clinlnvest, 71: 449

Libby, P. (1995). ‘‘Molecular bases of the acute coronary syndromes’’. Circulation; 91:2844–2850

McCaffrey, T.A. Du, B, Consigli S, Szabo P, Bray PJ, Hartner L, Weksler BB, Sanborn TA, Bergman G, and Bush HL : 1997. Genomic instability in the type II TGF-1 receptor gene in atherosclerotic and restenotic vascular cells; J Clin Invest 1997; 100:2182–2188

Renu Virmani , Frank, D. Kolodgie, Allen P. Burke, Aloke V. Finn, Herman, K. Gold, and Thomas, N . Tulenko. (2005) ‘‘Atherosclerotic plaque progression and vulnerability to rupture: angiogenesis is a source of intraplaque hemorrhage’’. ArteriosclerThrombVascBiol 2005; 25: 2054–61.

Zhi-Han Tang , Tao-Hua Li , Jie Zheng , Ting-Ting Li , Lu-Shan Liu , and Zhi-Sheng Jiang (2019). PCSK9: A novel inflammation modulator in atherosclerosis? J Cell Physiol, 234: 2345-23

Getz Max, L.A. Ebert, Vanessa F. Schmidt, Lena Pfaff, Anne von. Thaden, Melanie A. Kimm, and Moritz Wildgruber: (2021). ‘‘PCSK9 and lipid metabolism and atherosclerosis: animal models’’. Vessel Plus 2021;5:17

Förstermann U, Closs EI, and Pollock JS, Nakane M, Schwarz P, and Gath I: 1984. ‘‘Nitric oxide synthase isozymes. Characterization, purification, molecular cloning, and functions’’ Hypertension, 23: 1121–1131

Huang, Z. Hoffmann, F.W. Fay, J.D. Hashimoto, A.C. Chapagain, M.L. Kaufusi, (2012). Stimulation of unprimed macrophages with immune complexes triggers a low output of nitric oxide by calcium-dependent neuronal nitric-oxide synthase. The Journal of Biological Chemistry, 287: 4492–4502.

Hernández-Aguilera, A. Rodríguez-Gallego, E.Riera-Borrull, M. Luciano-Mateo, F. Camps, and J. Menéndez: 2013. Mitochondrial Dysfunction: A Basic Mechanism in Inflammation-Related Non-Communicable Diseases and Therapeutic Opportunities. Mediat. Inflamm; 201: 3,135698.

Orekhov, A.N. Nikiforov, N.N. Ivanova, E.A. and Sobenin, I.A. (2020). ‘‘Possible Role of Mitochondrial DNA Mutations in Chronification of Inflammation: Focus on Atherosclerosis’’ J. Clin. Med; 9:978.

Förstermann, U. Xia, and N. LiH. (2017)‘‘Roles of Vascular Oxidative Stress and Nitric Oxide in the Pathogenesis of Atherosclerosis’’ Circ. Res ; 120: 713–735

Kathirvel, Gopalakrishnan. Sivarajan, Kumarasamy. Shakila,Abdul-Majeed. Andrea, L. Kalinoski, Eric. E. Morgan, and Amira, F. Gohara (2012) ‘‘Targeted disruption of Adamts16 gene in a rat genetic model of hypertension’’ Proc, Natl Acad, Sci, USA 109:20555–20559. (doi:10.1073/pnas.1211290109)

Bina, Joe. Yasser, Saad. Seema, Dhindaw. Ovokeraye, H. Achinike, Truong. V. Luu, Kathirvel Gopalakrishnan. (2009). ‘‘Positional identification of variants of Adamts16 linked to inheritedhypertension’’,Hum,Mol,Genet; 18: 2825–2838. (doi:10.1093/hmg/ ddp218)

Ren, P. Zhang, LXu. G, Palmero. L.C. Albini, P.T. Coselli, J.S. and Shen, YH. (2013). ‘ADAMTS-1 and ADAMTS-4 levels are elevated in thoracic aortic aneurysms and dissections’’. Thorac Surg 2013; 95: 570–577. (doi:10.1016/j.athoracsur.2012.10.084)

Samani, N.J. andvan , der Harst. (2008). ‘‘Biological ageing and cardiovascular disease’’; Heart ; 94: 537–539.

Samani, N.J. Boultby, R. Butler, R. Thompson, J.R. and Goodall, A.H. (2001). ‘‘Telomere shortening in atherosclerosis’’; Lancet 2001; 358: 472–473

Epel, E.S. Merkin, S.S. Cawthon, R. Blackburn, E.H. Adler, N.E. Pletcher, M.J. Seeman, T.E. (2008). ‘‘The rate of leukocyte telomere shortening predicts mortality from cardiovascular disease in elderly’’ managing, 1: 81–88

Christopher, K. Steinberg, D. Yokode, M. Kita, T. Kawai, C. and JL, Witztum. (2001) ‘‘Atherosclerosis’’: The Road Ahead Cell; 104: 503–516

Celermajer, D.S. (1997). ‘‘Endothelial dysfunction: does it matter? Is it reversible’’? J Am, CollCardiol ; 30:325–333

Fichtlscherer S, Rosenberger G, Walter DH, S Breuer, S Dimmeler, A M Zeiher: 2000. Elevated C-reactive protein levels and impaired endothelial vasoreactivity in patients with coronary artery disease. Circulation 2000; 102: 1000–1006

C Bustos , M A Hernández-Presa, M Ortego, J Tuñón, L Ortega, G Hernández: 1998. HMG-CoA reductase inhibition by atorvastatin reduces neointimal inflammation in a rabbit model of atherosclerosis. J Am CollCardiol; 32:2057–2064

P. M. Ridker, N. Rifai, M. A. Pfeffer, F .Sacks, E. Braunwald, and Danielson, E. (1999). ‘‘Long-term effects of pravastatin on plasma concentration of C - reactive protein: The Cholesterol and Recurrent Events (CARE)’’Investigators Circulation, 100:230–235

Ridker, P.M. Rifai, N. and Lowenthal, S.P (2001). ‘‘Rapid reduction in C-reactive protein with cerivastatin among 785 patients with primary hypercholesterolemia’’ Circulation, 103:1191–1193

S. Marchesi , G. Lupattelli, G. Schillaci, A. R. Roscini, H. Sinzinger, and E. Mannarinoet (2000). ‘‘Short-term atorvastatin treatment improves endothelial function in hypercholesterolemic women’’, J CardiovascPharmacol; 36:617–621.

Sabatine, MS. (2019). PCSK9 inhibitors: ‘‘Clinical evidence and implementation’’. Nat Rev Cardiol ; 16 : 155-165

Bär, C. Bernardes, deJesus, B. Serrano, R. Tejera Ayuso, E. Formentini, I. de Martino, A. (2014). ‘‘Telomerase expression confers cardioprotection in the adult mouse heart after acute myocardial infarction’’. Nat. Commun 5: 5863.

AJ. Kattoor, NVK. Pothineni, D. Palagiri and JL. Mehta: 2017. “Oxidative Stress in Atherosclerosis,” Current Atherosclerosis Reports; 19: 77-82

Schneiderman, G. Goldstick, T.K. (1978) ‘‘Carbon monoxide-induced arterial wall hypoxia and atherosclerosis’’; Atherosclerosis; 30:1-15 doi: 10.1016/0021-9150(78)90148-x. PMID: 678310.

Wojciech, Suzanne. Salmon, Cecile. Maziere Jean-Claude, Maziere. Martine-Auclair, (1989). ‘‘Carbon disulfide modification and impaired catabolism of low density lipoprotein’’; Atherosclerosis; 78: 20-26,

Florencia, Harari . Lars, Barregard . Gerd, Östling . Gerd, Sallsten . Bo Hedblad , and Niklas, Forsgard. (2019) ‘‘Blood Lead Levels and Risk of Atherosclerosis in the Carotid Artery: Results from a Swedish Cohort’’. Environ Health Perspect; 127:127002. doi:10.1289/EHP5057

Petia, A. Abhyankar, L.N. Jones, MR. Guallar, E. Navas-Acien, A. Allen, NE. (2004). ‘‘Arsenic and atherosclerosis. Toxicology and Applied Pharmacology’’; 198:1016-1018. ,

Alexey, A. Tinkov, Tommaso Filippini., Olga, P. Ajsuvakova, Margarita. G. Skalnaya, Jan. Aaseth, and Geir, Bjørklund. (2018). ‘‘Cadmium and atherosclerosis: A review of toxicological mechanisms and a meta-analysis of epidemiologic studies’’. Environmental Research; 162:75-81

Peter, Jennrich. (2013). ‘‘The Influence of Arsenic, Lead, and Mercury on the Development of Cardiovascular Diseases’’, International Scholarly Research: 23: 470-476




How to Cite

Muhammad Naeem, Irum Naureen, Aisha Saleem, Rabia Yousaf, Shafa Fatima, Memoona Saher, Iza Tahreem, & Sehrish Rauf. (2022). Pathological Mechanism of Atherosclerosis. American Scientific Research Journal for Engineering, Technology, and Sciences, 89(1), 31–44. Retrieved from