31 American Academic Scientific Research Journal for Engineering, Technology, and Sciences ISSN (Print) 2313-4410, ISSN (Online) 2313-4402 http://asrjetsjournal.org/ Pathological Mechanism of Atherosclerosis Muhammad Naeem a , Irum Naureen b , Aisha Saleem c* , Rabia Yousaf d , Shafa Fatima e , Memoona Saher f , Iza Tahreem g , Sehrish Rauf h a Institute of Research and Information Mirpur, Azad Jammu and Kashmir b Assistant Professor, Minhaj University Lahore c,d,e,f,g,h M. Phil Researcher, Minhaj University Lahore a Email: physiologycardio@gmail.com b Email: dr.irumnaureen@mul.edu.pk c Email: aishasaleem160@gmail.com d Email: ryousaf219@gmail.com e Email: shafafatima829@gmail.com f Email: monagoraya7777@gmail.com g Email: izarana70@gmail.com h Email: sehrishrauf118@gmail.com Abstract 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. Keywords: Endothelial dysfunction; ROS; LDL; oxLDL; Macrophages; Foam cells; Plaque; NOS; hypercholesterolemia; microRNAs (miRNAs); proprotein convertase subtilisin/kexin type 9 (PCSK9) gene; telomere length (LTL). ------------------------------------------------------------------------ * Corresponding author. http://asrjetsjournal.org/ American Academic Scientific Research Journal for Engineering, Technology, and Sciences (ASRJETS) (2022) Volume 89, No 1, pp 31-44 32 1. Introduction According to WHO the Cardiovascular diseases (CVDs) cause nearly 17.9 million deaths per year. Atherosclerotic related vascular disease continues to be the leading cause of death in the Western world. The frequency of CVD in specific geographical populations provides evidence of inheritance. This also shows the prevalence and frequency of different risk factors among different populations. [1] In the lower and middle income countries the prevalence is also alarming. CVD is cause of 1/3 deaths in the world [2] . The underlying cause of the CVD process in coronary heart disease, stroke, and heart attack is atherosclerosis. Heart attack caused 17.3million death is 2008 and stroke cause 6,2million death. [3] The atherosclerosis causes coronary artery disease (CAD), cerebrovascular disease (Stroke), aorta and related arteries diseases including hypertension and peripheral vascular disease (PVD). The economic cost of the CVD is very devastating. [4] The risk factors fatty diet, smoking, genetic history, diabetes and hypertension and their frequency of persistence determine the appearance and progression of the atherosclerosis [5-6]. The atherosclerosis is fueled by low density lipoproteins is inflammatory process which harden the blood arteries even block them, and stop the oxygen supply to the tissues, due to disturbed blood supply to the area. [7] The modifiable risk factors are distributed with different frequency level in different regions [8] there is need to provide accessible interventions on the regional need basis to control the CVD [9] . There is need to deeply understand the atherosclerosis mechanism to develop interventions and therapeutics [10] . Many efforts from last decades made to understand the atherosclerosis but it is still considered difficult to treat. The basic mechanism which elucidated in literature starts with high level of LDL in the plasma, accumulation of LDL in vascular intima, oxidation of LDL by ROS in intima, endothelial expression of adhesive molecules, recruitment of macrophages to engulf the oxidized LDL (oxLDL), formation of foam cells, fatty streak appearance and plaque formation and rupture [11] . Many genes, molecules, cells, enzymes are involved in the whole process. Inflammation also play important role [12] . In order to prevent atherosclerosis from initiation to its progress we need to understand many underlying mechanisms to identify the possible intervention opportunities. Many years ago appearance of fatty streak in the blood vessels was considered as initiation point of atherosclerosis can be seen grossly or histologically, this can appear in any age [13] . Cellular and molecular research proved that fatty streak is only visible effect there are many processes behind it [14] . Now it is considered endothelial dysfunction is starting point of atherosclerosis which can be induced by atherosclerosis related risk factors [15] .Many industrial and traffic pollutants such as carbon monoxide (CO), Carbon disulfide (CS2) and toxic metals Lead (Pb), Cadmium (Cd), Arsenic (As) and Mercury (Hg) can play role in atherosclerosis. The CO cause hypoxia which cause oxidative stress and atherosclerosis. The CS2increase atherosclerosis by interfering with lipid metabolism and serum cholesterol, the toxic metals cause atherosclerosis by ROS and lipid peroxidation [80-81-82-83-84-85] . The diagram below shows the linear flow of cellular events happening in the atherosclerosis. American Academic Scientific Research Journal for Engineering, Technology, and Sciences (ASRJETS) (2022) Volume 89, No 1, pp 31-44 33 Figure 1: Linear Flow of Cellular Events in Atherosclerosis Risk factors external, genetic or internal can initiate endothelial dysfunction. Ds- Functioned endothelial has impaired Nitric oxide (NO) production with increased permeability to low density lipids (LDL) and imbalanced vasoconstriction and dilation, LDL transcytosis the endothelium in intima and binds wit extracellular proteoglycans. Reactive oxygen species (ROS) in intima oxidized the components of LDL to oxLDL. These oxLDL components induce the production of adhesion molecules, T cells and Monocytes adhere with dysfunctional endothelium diapedesis into intima, here monocytes differentiate into macrophages which engulf oxLDL and form the foam cells. Foam cells progress into fatty streak and calcified plaque narrowing the artery which ruptures to form clot through thrombosis. Artery Narrowing and blockage interrupt oxygenated blood to the tissue which cause different clinical manifestations in the form of cardiovascular disease. 2. Endothelial dysfunction Normal functional endothelium does not allow adhesion and penetration of blood cells (leucocytes and platelets) on its surface, balanced vasoconstriction and vasodilation, inhibition of vascular smooth cells proliferation and migration [16] . Some adhesive molecules are required for adhesion of blood cells with endothelium. These molecules are expressed on the time of demand under different circumstances. Atherosclerosis starts when endothelium becomes dysfunctional due to local or external factors. The atherosclerosis event occurs at the point of artery branch where endothelial cells face disturbed blood flow [17] . Natural vasoconstrictor angiotensin- II can produce reactive oxygen species (ROS) which can induce endothelial cells to express adhesive molecules [18] . Risk Factor Exposure •Sedentary life, Diabetes, Smoking, Hypertension, Hypercholesterima , Genetic history, Shear stress Endothelial Dysfunction •Increased permiability to LDL •Impaired NO production •Imbalanced vasoconstriction and vasodilation Accumulation of LDL in intima •Transcytosis •Interaction with Proteoglycans of matrix Oxidation of LDL •ROS •Lipid Peroxidation Recruitment of Leucocytes •T cells •Monocytes Foam cell formation •Differntiation of Monocyte to Macrophages •Uptake of oxLDL Plaque formation (Stability / Rupturing/ Thrombosis) American Academic Scientific Research Journal for Engineering, Technology, and Sciences (ASRJETS) (2022) Volume 89, No 1, pp 31-44 34 Defective production of Nitric Oxide (NO) plays important role in dysfunction of endothelial cells [19] . Endothelial dysfunction can be induced by many of the atherosclerotic risk factors [20] .Laminar blood flow keeps endothelium healthy, by maintaining its glycocalyx layer and coaxial alignment [21] , oscillatory shear stress with MEK5 signaling induce expression of eNOS its anti-atherogenic role is through NO [22] . A dysfunctional endothelium should have defective NO machinery and it can produce molecules which can help cells to adhere and penetrate inside the intima to initiate the atherosclerotic process. The morphological changes which occur in dysfunction endothelial cells increased permeability of the plasma membrane to LDL and VLDL, ApoB containing chylomicrons through transcytosis into the sub endothelial space [23-24] .Endothelial cells produce NO from L-Arginine with the help of Nitric Oxide Synthase (NOS) enzyme. Shear stress increase eNOS production, caveolin-1 protein inhibit activity of eNOS, calcium ions activate eNOS. Asymmetric dimethylarginine (ADMA) inhibits NO. Similarly, isoprenoid geranylgeranyl pyrophosphates, intermediate of cholesterol synthesis pathway also inhibit eNOS [25-26] . Mitochondrial oxidative stress reduces the NO production and enhances the inflammation and atherosclerosis [61] . In the vascular wall endothelial cells mitochondrial dysfunction is very important it puts its contribution through oxidative stress, impaired mitophagy and metabolic breakdown can be therapeutically targeted, it also need research to elaborate clear mechanism [62- 63] . 3. Intake and Oxidation of LDL Fatty diet can increase level of LDL in plasma when reached the site of endothelial dysfunction it transcytosis to the intima, if cross a threshold level can be pathological [27] the ApoB100 component of the LDL remained bind with the proteoglycan matrix of the intima [28] . Under ROS, these LDL are oxidized by the lipid peroxidation process [29] these oxidized components of the LDL can serve as epitopes for the immune system [23] lipoxygenase and phospholipase A-2 enzymes alter LDL to oxLDL [31] .These modifications make LDL higher in density, degrade ApoB, amend lysine residue of ApoB and hydrolyzing phosphatidylcholine [32] Polyunsaturated fatty acids are more oxidized than monounsaturated fatty acids. [33] 4. Expression of adhesion molecules The oxLDL components now can induce expression of different molecules by the endothelial cells via LOX-1 receptor. LOX-1 is endothelial receptor for oxidized LDL [34] it is over expressed in atherosclerotic condition; this is lectin like receptor. The oxidized components of the LDL like lyso phosphatidyl choline (PC), oxidized phospholipids, 9-hydroxyeicosatetraenoic acid, Modified Apo B, cholesterol, oxysterols and other oxidized lipids of LDL each can exert Proatherogenic Effects in different ways by interacting with endothelial cells, monocytes and T cells [35] . The endothelial cells are induced by oxLDL to produce adhesion molecules such as intracellular adhesion molecule -1 (ICAM-1) and vascular cell adhesion molecule (VCAM-1) [36] these molecules allow leucocytes to attach on the surface of endothelium for future infiltration into the intima. 5. Recruitment and Differentiation of Leucocytes Normal endothelial cells have NO which stops monocytes to attach with endothelial cells. OxLDL reduce the American Academic Scientific Research Journal for Engineering, Technology, and Sciences (ASRJETS) (2022) Volume 89, No 1, pp 31-44 35 NO production in the endothelial cells, it encourages monocytes to attach with endothelium and ICAM-1 and VCAM-1 adhere them with endothelial cell [37] . Endothelial cells also express E-Selectin and P-Selectin molecules on its surface which helps in rolling of leucocytes on endothelium for infiltration into the intima [38] in response to Fractkalkine, MCP-1 and RANTES (Ccl5) [39] . This migration is in sequence chemoattractant MCP- 1 (monocyte chemotactic protein--1) attract leucocytes, CCR-2 is receptor of MCP-1, VCAM-1 firmly adheres leucocytes, P and E Selectins helps in rolling. By this way Monocytes and T cells diapedesis into intima. Inside the intima migrated monocytes differentiate into macrophage. The cytokine Macrophage-colony stimulating factor (M-CSF) produced by endothelial cells and also stromal cells (fibroblast cells) [40] differentiate monocytes to macrophages. Now macrophages are highly efficient for taking oxLDL through pattern recognition receptor, i.e. Scavenger receptors (SR-A), toll-like receptors and CD36 [41-42] . These differentiated macrophages either pro-inflammatory with M-1 phenotype or anti-inflammatory M-2 phenotype, depending upon the signals, M-1 predominates in atheroma progression phase and M-2 is abundant at the time of atheroma regression [43] . Th1 cells produce LPS (lipopolysaccharide), Interferon-g (IFN)-g and Tissue necrosis factor alpha (TNF-a) are pro-inflammatory and induce M-1. Interleukin-4 (IL-4), Interleukin-10, Interleukin-13 and tumor growth factor beta (TFG)-b are anti-inflammatory and are produced by Th-2 cells [44] . Other pro-inflammatory biomarkers associated with atherosclerosis are C reactive protein (CRP) of Hepatocyte, Tumor necrosis factor alpha and Interleuken-1 (IL-1), Interleuken-12 (IL-12), Interleuken-15 (IL-15), Interleuken-8 (IL-8) by Macrophage and Interleuken-6 (IL-6) by macrophages and endothelial cells act as acute phase reactant, cytokines, and chemokines [45] . 6. Uptake of oxLDL and Formation of Foam cells The scavenger receptors (SR)-A, −BI on the surface of the macrophage intake oxLDL these modified derivatives inside the macrophage stops the expression of LDL receptors but not the scavenger receptors [46] . The Liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs) are transcription factors, efficiently work for cholesterol and fatty acids homeostasis inside the macrophages, and prevent foam cell formation and development of atherosclerosis [47], the athero-protective mechanism works as cholesterol efflux. Smooth muscle cells of the vascular walls can also express the receptors for the LDL and can form foam cells [48] . Many micro RNAs (miRNAs) regulate the genes involved in the lipid up taking in the macrophages and conversion to foam cells [49] . ATP binding cassette transporter A1 (ABCA1) expressed in liver and macrophages is plasma membrane lipid pump, when its level is decreased lipids are trapped inside the macrophage and convert to foam cell [50] . Smooth muscle cells form a fibrous capsule around these foam cells and fatty streak is formed, which can be seen histologically. The lipid loaded macrophages cells undergoes apoptosis mediated by P 53 and FAS [51] , however in endothelial dysfunctional cells miR-590 inhibits the oxLDL induced expression of apoptotic machinery factors P 53 and BAX. Apoptotic machinery disturbance enables now macrophages engorged with loaded lipids and endothelial cells to progress towards plaque formation. 7. Plaque formation and rupturing This fatty streak can be a physiological process to protect the tissue from cytotoxic effects of the oxLDL [52] , the American Academic Scientific Research Journal for Engineering, Technology, and Sciences (ASRJETS) (2022) Volume 89, No 1, pp 31-44 36 progression of streak depends upon the persistence of the risk factors exposure [53] , and regression also depends on the balance between level of LDL in plasma and intima. T cells which produce the IFN-gamma plays role in plaque destabilization by reducing fibrous cap [54] , Macrophages, Th-3 cells and smooth muscle cells can express TGF-beta which is involved in plaque stabilization by stimulating the collagen synthesis and cap formation [55] with time the focal calcification of plaque occurs. Large number of macrophages along with pro- inflammatory cytokines accumulate in the vascular wall late in the atherosclerosis secreting the matrix metalloproteinase (MMPs), degradation of the extracellular matrix occurs, rupture the plaque, cause bleeding and thrombosis [56] . This disruption and thrombotic event can lead to the clinical manifestations in the form of cardiovascular diseases. 8. Genes, Enzymes, Cytokines, Chemokines of atherosclerosis Proprotein convertase subtilisin/kexin type 9 (PCSK9) gene located on the short arm of chromosome 1 near the familial hypercholesterolemia, mainly responsible for plasma level of LDL especially cholesterol in LDL [57-58] by controlling LDL receptors (LDLr). NOS genes has three isoforms, located on 12, 17 and 7, isoform NOS3 express membrane bound endothelial NOS enzymes [59] , in macrophages isoform NOS2 is expressed to form soluble NOS enzyme [60] . ADAMTS-16 is quantitative trait gene has been investigated for its role in the regulation of blood pressure [64-65] , which is risk factor in the form of hypertension, however ADAMTS4 can reduce the monocyte infiltration in intima [66] . Telomere on the end of chromosomes have repetitive sequence of (TTAGGG)n, telomere length (LTL) differs in tissues. In leucocytes in the peripheral tissues LTL is associated with the CVD risk [67] LTL shortening plays role in atherosclerosis and age related CVD [68-69] . Other atherosclerotic genes are 12/15-LO, M-CSF, MCP-1, CCR2, P- and E-selectin, CXCR-2, SR-A, CD36, IFNg receptor, CD154 and IL-10, however Paraoxinase, Apo A-I, PPARg and SR-B1 are antiatherogenic genes [70] . 9. Diagnosis and clinical interventions Initiating step in atherosclerosis i.e. Endothelial dysfunction can be detected by fluid mediated dilation (FMD) and acetylcholine test, the level of CRP test also relates with the endothelial dysfunction and cardiac event [71- 72] .Other noninvasive method such as Doppler ultrasound studies are in use to detect the endothelial dysfunction. Lipid lowering therapy (HMG-CoA), reductase inhibitors as in case of mostly used statins can correct endothelial function, Atorvastatin and pravastatin treatment with time can reduce the level of CRP [73-74-75-76] . PCSK9 inhibitor armamentarium clinically is in use and can reduce the cholesterol level in plasma [77] . The telomere based therapies in the experimental mice showed improved cardiac functioning [78] , this approach can be a prospective therapy for non-modifiable factor such as age. 10. Risk management interventions In the effort to manage the risks for the atherosclerosis there is need to lessen the intensity of exposure to the atherogenic risk factors i.e. elevated LDL, Smoking, Sedentary life, Alcohol use, diabetes, hypertension, genetic background. Among these age and genetic back ground are non-modifiable. But other factors can be managed by the social and clinical interventions. Among these are adaptation to healthy life style to reduce the chances of American Academic Scientific Research Journal for Engineering, Technology, and Sciences (ASRJETS) (2022) Volume 89, No 1, pp 31-44 37 endothelial dysfunction and initiation of atherosclerosis. Second option is usage or exposure to the athero- protective factors which are exercise and use of HDL and others which can contribute to the “reverse cholesterol transport” mechanism 11. Conclusion Consistent exposure to the atherosclerotic risk factors either external or inside the body intimate endothelial dysfunction. This first step of atherosclerosis is detectable by invasive and noninvasive methods and correlate with the risk factors presence. Early detection along with risk factor management and adaptation to the athero- protective clinical interventions can restore the endothelial dysfunction. Once dysfunctional endothelial inhibits NO production and starts expression of adhesive molecules, now leucocytes adhere and diapedesis in intima, differentiate into foam cells, fatty steak, calcified, rupture and thrombotic event occurs with clinical manifestations in the form of cardiovascular diseases. References [1] Mendis S, Puska P, and Norrving B: 2011. ‘‘Global Atlas on Cardiovascular Disease Prevention and Control. Editors’’. World Health Organization, Geneva 2011. [2] 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 [3]Causes of death: 2008. ‘‘World Health Organization, Geneva,’’ http://www.who.int/healthinfo/ global_burden_disease/ cod_2008_sources_methods.pdf. [4] 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. [5] MD, Ashen. R.S.Blumenthal, (2005). ‘‘Low HDL Cholesterol Levels New England J of Medicine’’, 353:1252–1260. [6] 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 [7] 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 https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000000350 https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000000350 https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000000350 https://pubmed.ncbi.nlm.nih.gov/?term=Kotseva+K&cauthor_id=20577089 https://pubmed.ncbi.nlm.nih.gov/20577089/#affiliation-1 https://pubmed.ncbi.nlm.nih.gov/?term=Wood+D&cauthor_id=20577089 https://pubmed.ncbi.nlm.nih.gov/?term=De+Backer+G&cauthor_id=20577089 https://pubmed.ncbi.nlm.nih.gov/?term=De+Bacquer+D&cauthor_id=20577089 https://pubmed.ncbi.nlm.nih.gov/?term=Py%C3%B6r%C3%A4l%C3%A4+K&cauthor_id=20577089 https://pubmed.ncbi.nlm.nih.gov/?term=Reiner+Z&cauthor_id=20577089 https://pubmed.ncbi.nlm.nih.gov/?term=Rana+JS&cauthor_id=27028434 https://pubmed.ncbi.nlm.nih.gov/?term=Prendergast+C&cauthor_id=27028434 https://pubmed.ncbi.nlm.nih.gov/?term=McGill+H&cauthor_id=27028434 https://pubmed.ncbi.nlm.nih.gov/?term=Carr+JJ&cauthor_id=27028434 https://pubmed.ncbi.nlm.nih.gov/?term=Liu+K&cauthor_id=27028434 American Academic Scientific Research Journal for Engineering, Technology, and Sciences (ASRJETS) (2022) Volume 89, No 1, pp 31-44 38 Determinants of Atherosclerosis in Youth Study 1985– 1995’’, Prevention and Control 2005; 1:3–15. [8] 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 [9]Peter, Jennrich. (2013). ‘‘The Influence of Arsenic, Lead, and Mercury on the Development of Cardiovascular Diseases’’, International Scholarly Research: 23: 470-476 https://doi.org/10.5402/2013/234034. [10] 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, https://doi.org/10.1016/S0140- 6736(10)62036-3. [11] Christopher, K. Steinberg, D. Yokode, M. Kita, T. Kawai, C. and J. L. Witztum. (2001). ‘‘Atherosclerosis’’: The Road Ahead, 104: 503–516 [12] Kobiyama,. K and Ley, K. (2018). ‘‘Atherosclerosis’’, Circ Res; 123: 1118-1120, [13] 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 [14] 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 [15] 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 [16] 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 [17] Kinlay S, Libby P. Ganz P. (2001) ‘‘Endothelial function and coronary artery disease’’. CurrOpinLipidol. 12:383–389 [18] Li, H. Cybulsky, M.I. Gimbrone, M.A. Jr. Libby, p. Watanabe, T. Fan, J. et al. (1993) ‘‘An atherogenic https://pubmed.ncbi.nlm.nih.gov/?term=Chow+CK&cauthor_id=24002282 https://pubmed.ncbi.nlm.nih.gov/?term=Teo+KK&cauthor_id=24002282 https://pubmed.ncbi.nlm.nih.gov/?term=Rangarajan+S&cauthor_id=24002282 https://pubmed.ncbi.nlm.nih.gov/?term=Islam+S&cauthor_id=24002282 https://pubmed.ncbi.nlm.nih.gov/?term=Gupta+R&cauthor_id=24002282 https://pubmed.ncbi.nlm.nih.gov/?term=Avezum+A&cauthor_id=24002282 https://pubmed.ncbi.nlm.nih.gov/?term=Avezum+A&cauthor_id=24002282 https://pubmed.ncbi.nlm.nih.gov/?term=Finucane+MM&cauthor_id=21295844 https://pubmed.ncbi.nlm.nih.gov/?term=Lin+JK&cauthor_id=21295844 https://pubmed.ncbi.nlm.nih.gov/?term=Singh+GM&cauthor_id=21295844 https://pubmed.ncbi.nlm.nih.gov/?term=Paciorek+CJ&cauthor_id=21295844 https://pubmed.ncbi.nlm.nih.gov/?term=Cowan+MJ&cauthor_id=21295844 https://doi.org/10.1016/S0140-6736(10)62036-3 https://doi.org/10.1016/S0140-6736(10)62036-3 https://www.ncbi.nlm.nih.gov/pubmed/?term=Holman%20RL%5BAuthor%5D&cauthor=true&cauthor_uid=13520905 https://www.ncbi.nlm.nih.gov/pubmed/?term=Strong%20JP%5BAuthor%5D&cauthor=true&cauthor_uid=13520905 American Academic Scientific Research Journal for Engineering, Technology, and Sciences (ASRJETS) (2022) Volume 89, No 1, pp 31-44 39 diet rapidly induces VCAM-1, a cytokine regulatable mononuclear leukocyte adhesion molecule, in rabbit endothelium’’. ArteriosclerThromb. 13: 197–204 [19] Griendling, K.K. Ushio-Fukai, M. Lassegue, B.R W Alexander, Touyz, R.M. Berry, C.et al. (1997) ‘‘Angiotensin II signaling in vascular smooth muscle: new concepts’’. Hypertension 1997;29: 366–373 [20] 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. [21] 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. [22] R. Ross. (1986). “The pathogenesis of atherosclerosis an update,” The New England Journal of Medicine, 314: 488–500, [23] M. Khazaei, F.Moien-afshari, and I. Laher (2008). “Vascular endothelial function in health and diseases,” Pathophysiology, 15: 49–67, [24] 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 [25] 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 [26]Cooke, J.P. (2000). ‘‘Does ADMA cause endothelial dysfunction’’? ArteriosclerThrombVascBi;20:2032–2037 [27] Lu¨scher, T.F. and Barton, M. (1997). Biology of the endothelium, ClinCardiol; 20:3-10. [28] JL. Goldstein and M.S. Brown (2015). “A century of cholesterol and coronaries: from plaques to genes to statins’’ 2015; 16:161–172, [29] 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, [30] 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 American Academic Scientific Research Journal for Engineering, Technology, and Sciences (ASRJETS) (2022) Volume 89, No 1, pp 31-44 40 [31] 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, [32] 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, [33] 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 [34] 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 [35] 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 [36] Christopher, K. Steinberg, D. Yokode, M. Kita, T. Kawai, C. and J. L Witztum. (2001). Atherosclerosis: The Road Ahead Cell, 104:503–516 [37] 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 [38] 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 [39] Springer, T.A. (1994). ‘‘Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm, Cell’’. 76:301–314. [40] Zernecke, A. Shagdarsuren, E. and Weber, C. (2008). ‘Chemokines in atherosclerosis: an update’’. ArteriosclerThromb Vasc Biol, 28: 1897–1908. [41] Hazen, S. L. (2008). ‘‘Oxidized phospholipids as endogenous pattern recognition ligands in innate immunity’’ Journal of Biological Chemistry, 283: 15527–15531. [42] Libby, P. (2002) ‘‘Inflammation in atherosclerosis; Nature’’, 420:868–874. doi:10.1038/nature01323 [43] Orecchioni, Marco. Yanal,Ghosheh. Akula Bala, Pramod. Klaus Ley,Checkouri, E. and Blanchard V. https://pubmed.ncbi.nlm.nih.gov/?term=Berb%C3%A9e+JFP&cauthor_id=28655430 https://pubmed.ncbi.nlm.nih.gov/?term=Mol+IM&cauthor_id=28655430 https://pubmed.ncbi.nlm.nih.gov/?term=Milne+GL&cauthor_id=28655430 https://pubmed.ncbi.nlm.nih.gov/?term=Pollock+E&cauthor_id=28655430 https://pubmed.ncbi.nlm.nih.gov/?term=Hoeke+G&cauthor_id=28655430 https://pubmed.ncbi.nlm.nih.gov/?term=L%C3%BCtjohann+D&cauthor_id=28655430 https://pubmed.ncbi.nlm.nih.gov/?term=L%C3%BCtjohann+D&cauthor_id=28655430 American Academic Scientific Research Journal for Engineering, Technology, and Sciences (ASRJETS) (2022) Volume 89, No 1, pp 31-44 41 (2019). ‘‘Macrophage Polarization: Different Gene Signatures in M1(LPS+) vs. Classically and M2(LPS–) vs. Alternatively Activated Macrophages’’ Frontiers in Immunology, 10:84-89 https://www.frontiersin.org/article/10.3389/fimmu.2019.01084 [44] 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 https://www.frontiersin.org/article/10.3389/fimmu.2019.02217 [45] 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 [46] Brown, M.S and Goldstein, JL. (1986) ‘‘A receptor-mediated pathway for cholesterol homeostasis’’ Science; 232: 34–47. [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. [48] Collin, S.P. Carleena, O. Joshua, A.D. Gordon, A.F. (2019). ‘‘Pathways of smooth muscle foam cell formation in atherosclerosis’’ CurrOpinLipidol ; 30:117e124 [49] 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. [50] 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. [51] 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. [52] Hesslcr, J.R. Morel, D.W. Lewis, L.J. and Chiaolin, GM. (1983). ‘Lipoprotein oxid;ition and lipoprotein-induced cytotoxicity’’ . Arteriosclerosis; 3:215 [53] 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 [54] Libby, P. (1995). ‘‘Molecular bases of the acute coronary syndromes’’. Circulation; 91:2844–2850 [55] McCaffrey, T.A. Du, B, Consigli S, Szabo P, Bray PJ, Hartner L, Weksler BB, Sanborn TA, Bergman https://www.frontiersin.org/article/10.3389/fimmu.2019.01084 https://www.frontiersin.org/article/10.3389/fimmu.2019.02217 https://pubmed.ncbi.nlm.nih.gov/?term=An+LN&cauthor_id=24675724 https://pubmed.ncbi.nlm.nih.gov/?term=Wang+GK&cauthor_id=24675724 https://pubmed.ncbi.nlm.nih.gov/24675724/#affiliation-1 https://pubmed.ncbi.nlm.nih.gov/?term=Zhu+JQ&cauthor_id=24675724 https://pubmed.ncbi.nlm.nih.gov/?term=Li+Q&cauthor_id=24675724 https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+YY&cauthor_id=24675724 https://pubmed.ncbi.nlm.nih.gov/24675724/#affiliation-3 https://pubmed.ncbi.nlm.nih.gov/?term=Canfr%C3%A1n-Duque+A&cauthor_id=28674080 https://pubmed.ncbi.nlm.nih.gov/?term=Rotllan+N&cauthor_id=28674080 https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+X&cauthor_id=28674080 https://pubmed.ncbi.nlm.nih.gov/?term=Fern%C3%A1ndez-Fuertes+M&cauthor_id=28674080 https://pubmed.ncbi.nlm.nih.gov/?term=Ram%C3%ADrez-Hidalgo+C&cauthor_id=28674080 https://pubmed.ncbi.nlm.nih.gov/?term=Ram%C3%ADrez-Hidalgo+C&cauthor_id=28674080 https://pubmed.ncbi.nlm.nih.gov/?term=Araldi+E&cauthor_id=28674080 https://pubmed.ncbi.nlm.nih.gov/?term=Li+JM&cauthor_id=26648441 https://pubmed.ncbi.nlm.nih.gov/?term=Zhou+QL&cauthor_id=26648441 https://pubmed.ncbi.nlm.nih.gov/?term=Li+GY&cauthor_id=26648441 https://pubmed.ncbi.nlm.nih.gov/?term=Zeng+J&cauthor_id=26648441 https://pubmed.ncbi.nlm.nih.gov/?term=Zhao+J&cauthor_id=26648441 American Academic Scientific Research Journal for Engineering, Technology, and Sciences (ASRJETS) (2022) Volume 89, No 1, pp 31-44 42 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 [56] 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. [57] 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 [58] 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 https://dx.doi.org/10.20517/2574-1209.2020.70 [59] 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 [60] 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. [61] 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. [62] 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. [63] 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 [64] 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) [65] 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) https://pubmed.ncbi.nlm.nih.gov/?term=Virmani+R&cauthor_id=16037567 https://pubmed.ncbi.nlm.nih.gov/16037567/#affiliation-1 https://pubmed.ncbi.nlm.nih.gov/?term=Kolodgie+FD&cauthor_id=16037567 https://pubmed.ncbi.nlm.nih.gov/?term=Burke+AP&cauthor_id=16037567 https://pubmed.ncbi.nlm.nih.gov/?term=Finn+AV&cauthor_id=16037567 https://pubmed.ncbi.nlm.nih.gov/?term=Gold+HK&cauthor_id=16037567 https://pubmed.ncbi.nlm.nih.gov/?term=Tulenko+TN&cauthor_id=16037567 https://pubmed.ncbi.nlm.nih.gov/?term=Tulenko+TN&cauthor_id=16037567 https://pubmed.ncbi.nlm.nih.gov/?term=Tang+ZH&cauthor_id=30246446 https://pubmed.ncbi.nlm.nih.gov/?term=Li+TH&cauthor_id=30246446 https://pubmed.ncbi.nlm.nih.gov/?term=Zheng+J&cauthor_id=30246446 https://pubmed.ncbi.nlm.nih.gov/?term=Li+TT&cauthor_id=30246446 https://pubmed.ncbi.nlm.nih.gov/?term=Liu+LS&cauthor_id=30246446 https://pubmed.ncbi.nlm.nih.gov/30246446/#affiliation-1 https://pubmed.ncbi.nlm.nih.gov/?term=Jiang+ZS&cauthor_id=30246446 https://www.jacc.org/doi/10.1016/j.jacbts.2021.06.006 https://www.jacc.org/doi/10.1016/j.jacbts.2021.06.006 https://www.jacc.org/doi/10.1016/j.jacbts.2021.06.006 https://www.jacc.org/doi/10.1016/j.jacbts.2021.06.006 https://www.jacc.org/doi/10.1016/j.jacbts.2021.06.006 https://www.jacc.org/doi/10.1016/j.jacbts.2021.06.006 https://dx.doi.org/10.20517/2574-1209.2020.70 https://pubmed.ncbi.nlm.nih.gov/?term=Gopalakrishnan+K&cauthor_id=23185005 https://pubmed.ncbi.nlm.nih.gov/?term=Kumarasamy+S&cauthor_id=23185005 https://pubmed.ncbi.nlm.nih.gov/?term=Abdul-Majeed+S&cauthor_id=23185005 https://pubmed.ncbi.nlm.nih.gov/?term=Kalinoski+AL&cauthor_id=23185005 https://pubmed.ncbi.nlm.nih.gov/?term=Kalinoski+AL&cauthor_id=23185005 https://pubmed.ncbi.nlm.nih.gov/?term=Morgan+EE&cauthor_id=23185005 https://pubmed.ncbi.nlm.nih.gov/?term=Gohara+AF&cauthor_id=23185005 https://pubmed.ncbi.nlm.nih.gov/?term=Joe+B&cauthor_id=19423552 https://pubmed.ncbi.nlm.nih.gov/?term=Saad+Y&cauthor_id=19423552 https://pubmed.ncbi.nlm.nih.gov/?term=Dhindaw+S&cauthor_id=19423552 https://pubmed.ncbi.nlm.nih.gov/?term=Achinike+OH&cauthor_id=19423552 https://pubmed.ncbi.nlm.nih.gov/?term=Luu+TV&cauthor_id=19423552 https://pubmed.ncbi.nlm.nih.gov/?term=Gopalakrishnan+K&cauthor_id=19423552 https://pubmed.ncbi.nlm.nih.gov/?term=Gopalakrishnan+K&cauthor_id=19423552 American Academic Scientific Research Journal for Engineering, Technology, and Sciences (ASRJETS) (2022) Volume 89, No 1, pp 31-44 43 [66] 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) [67] Samani, N.J. andvan , der Harst. (2008). ‘‘Biological ageing and cardiovascular disease’’; Heart ; 94: 537–539. [68] Samani, N.J. Boultby, R. Butler, R. Thompson, J.R. and Goodall, A.H. (2001). ‘‘Telomere shortening in atherosclerosis’’; Lancet 2001; 358: 472–473 [69] 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 [70] Christopher, K. Steinberg, D. Yokode, M. Kita, T. Kawai, C. and JL, Witztum. (2001) ‘‘Atherosclerosis’’: The Road Ahead Cell; 104: 503–516 [71] Celermajer, D.S. (1997). ‘‘Endothelial dysfunction: does it matter? Is it reversible’’? J Am, CollCardiol ; 30:325–333 [72] 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 [73] 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 [74] 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 [75] 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 [76] 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. [77] Sabatine, MS. (2019). PCSK9 inhibitors: ‘‘Clinical evidence and implementation’’. Nat Rev Cardiol ; 16 : 155-165 [78] Bär, C. Bernardes, deJesus, B. Serrano, R. Tejera Ayuso, E. Formentini, I. de Martino, A. (2014). https://pubmed.ncbi.nlm.nih.gov/?term=Breuer+S&cauthor_id=10961964 https://pubmed.ncbi.nlm.nih.gov/?term=Dimmeler+S&cauthor_id=10961964 https://pubmed.ncbi.nlm.nih.gov/?term=Zeiher+AM&cauthor_id=10961964 https://pubmed.ncbi.nlm.nih.gov/?term=Bustos+C&cauthor_id=9857893 https://pubmed.ncbi.nlm.nih.gov/?term=Hern%C3%A1ndez-Presa+MA&cauthor_id=9857893 https://pubmed.ncbi.nlm.nih.gov/?term=Ortego+M&cauthor_id=9857893 https://pubmed.ncbi.nlm.nih.gov/?term=Tu%C3%B1%C3%B3n+J&cauthor_id=9857893 https://pubmed.ncbi.nlm.nih.gov/?term=Ortega+L&cauthor_id=9857893 https://pubmed.ncbi.nlm.nih.gov/?term=Hern%C3%A1ndez+G&cauthor_id=9857893 https://pubmed.ncbi.nlm.nih.gov/?term=Ridker+PM&cauthor_id=10411845 https://pubmed.ncbi.nlm.nih.gov/?term=Rifai+N&cauthor_id=10411845 https://pubmed.ncbi.nlm.nih.gov/?term=Pfeffer+MA&cauthor_id=10411845 https://pubmed.ncbi.nlm.nih.gov/?term=Sacks+F&cauthor_id=10411845 https://pubmed.ncbi.nlm.nih.gov/?term=Braunwald+E&cauthor_id=10411845 https://pubmed.ncbi.nlm.nih.gov/?term=Marchesi+S&cauthor_id=11065222 https://pubmed.ncbi.nlm.nih.gov/?term=Lupattelli+G&cauthor_id=11065222 https://pubmed.ncbi.nlm.nih.gov/?term=Schillaci+G&cauthor_id=11065222 https://pubmed.ncbi.nlm.nih.gov/?term=Roscini+AR&cauthor_id=11065222 https://pubmed.ncbi.nlm.nih.gov/?term=Sinzinger+H&cauthor_id=11065222 https://pubmed.ncbi.nlm.nih.gov/?term=Mannarino+E&cauthor_id=11065222 American Academic Scientific Research Journal for Engineering, Technology, and Sciences (ASRJETS) (2022) Volume 89, No 1, pp 31-44 44 ‘‘Telomerase expression confers cardioprotection in the adult mouse heart after acute myocardial infarction’’. Nat. Commun 5: 5863. [79] AJ. Kattoor, NVK. Pothineni, D. Palagiri and JL. Mehta: 2017. “Oxidative Stress in Atherosclerosis,” Current Atherosclerosis Reports; 19: 77-82 [80] 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. [81] 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, https://doi.org/10.1016/0021-9150(89)90225-6 [82] 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 [83] 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. ,https://doi.org/10.1016/j.taap.2003.10.018. [84]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 https://doi.org/10.1016/j.envres.2018.01.008. [85] Peter, Jennrich. (2013). ‘‘The Influence of Arsenic, Lead, and Mercury on the Development of Cardiovascular Diseases’’, International Scholarly Research: 23: 470-476 https://doi.org/10.5402/2013/234034. https://doi.org/10.1016/0021-9150(89)90225-6 https://pubmed.ncbi.nlm.nih.gov/?term=Harari+F&cauthor_id=31808705 https://pubmed.ncbi.nlm.nih.gov/?term=Barregard+L&cauthor_id=31808705 https://pubmed.ncbi.nlm.nih.gov/?term=%C3%96stling+G&cauthor_id=31808705 https://pubmed.ncbi.nlm.nih.gov/?term=Sallsten+G&cauthor_id=31808705 https://pubmed.ncbi.nlm.nih.gov/31808705/#affiliation-1 https://pubmed.ncbi.nlm.nih.gov/?term=Hedblad+B&cauthor_id=31808705 https://pubmed.ncbi.nlm.nih.gov/31808705/#affiliation-2 https://pubmed.ncbi.nlm.nih.gov/?term=Forsgard+N&cauthor_id=31808705 https://pubmed.ncbi.nlm.nih.gov/?term=Forsgard+N&cauthor_id=31808705 https://doi.org/10.1016/j.taap.2003.10.018 https://doi.org/10.1016/j.envres.2018.01.008