Air pollution causes atherosclerosis through inducing pathological changes in the blood (a new perspective)

Bioscience Hypotheses (2008) 1, 301e305

available at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/bihy

Air pollution causes atherosclerosis through inducing pathological changes in the blood (a new perspective) Mojtaba Rismanchi* Medical School, Shiraz University of Medical Sciences, Zand Avenue, Shiraz, Iran Received 10 June 2008; accepted 26 June 2008

KEYWORDS Air pollution; Oxidation; LDL; Alpha-1 antitrypsin; Elastase; Atherosclerosis

Abstract Atherosclerosis has been correlated with air pollution. However, the air pollution’s atherogenic mechanism is not clear yet. This hypothesis proposes an atherogenic mechanism for air pollution and claims that the air pollution changes the physiological properties of the blood and then these changes promote the formation of atherosclerotic plaques. The first atherogenic effect of air pollution is hypothesized to be the inactivation of alpha-1 antitrypsin molecules in plasma via oxidation. In the next step, oxidized alpha-1 antitrypsin attaches LDL and forms a complex in the blood stream of lungs. This complex goes through intima with the action of a mediator and when in the vascular wall it is catabolised 4 times more effectively than LDL alone. The result is the formation of foamy cells that characterize atherosclerosis. In this hypothesis, it is also reasoned that the mediator of the complex passage through the arterial walls is elastase. At the end, this hypothesis argues on the bases of its documents that the mean distribution of atherosclerosis in the body obeys a pattern of decreased intensity centrifugally from lungs. ª 2008 Elsevier Ltd. All rights reserved.

Introduction Cardiovascular diseases are the major source of morbidity and mortality throughout the world particularly in western industrialized countries, and atherosclerosis is undoubtedly the main underlying pathology [1]. Arteries undergo gradual changes as we age, and it is difficult to realize when the normal growth processes give their way to the processes of pathogenesis. Each artery has a specific aging pattern.

* Tel.: þ98 9173073027. E-mail address: [email protected]

Coronary arteries are greatly predisposed to such pathologies specifically atherosclerosis [2]. Atherosclerosis first appears in the vascular intima, and involves some stages such as infiltration of inflammatory leukocytes, accumulation of macrophages and foam cells, proliferation of smooth muscle cells, accumulation of extracellular matrix and lipids, disruption of the endothelial surface, hemorrhage into the plaque and thrombus formation [3]. Thickening of the intima in the way mentioned above is known as a normal phenomenon of aging [2]. The formation of atherosclerotic plaques is directly related to the oxidation of LDL [4e6]. Oxidation of LDLs causes enhanced lipid uptake by macrophages, leading to the formation of foam cells [4]. But how

1756-2392/$ - see front matter ª 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.bihy.2008.06.012

302 this molecule oxidation and lipid uptake occurs is something which varies according to the cause of atherosclerosis. There is ample epidemiological and experimental evidence for air pollution to be nominated as a cause of atherosclerosis [7e 10]. However, the underlying mechanism for atherogenesis of air pollution is not clearly stated yet. This hypothesis explains a possible mechanism for it.

M. Rismanchi infection or inflammation [12,24]. It has protective effects against especially gram negative bacteria [12]. But once its regulators fail to function, it causes deleterious effects on the body such as emphysema in AAT deficient people [13]. Studies have correlated coronary artery disease (CAD) with elastase concentration in plasma. These studies state that elastase concentration is a ‘‘sensitive diagnostic marker of CAD’’ [27].

Background of hypothesis Elastase and endothelial damage Air pollution Concentrations of oxidants and pro-oxidants in ambient air pollution, such as particulate components (particulate matters, transition metals, reactive organic compounds), and gases such as ozone (O3) or nitrogen oxides (NO, NO2) promote oxidative stress and respiratory inflammatory responses [7,11]. Pulmonary responses also lead to subclinical systemic inflammation through cytokines and chemokines [7].

Air pollution and alpha-1 antitrypsin Alpha-1 antitrypsin (AAT) - a 52 kDa protein - is an acute phase protein and the most abundant circulating serine proteinase inhibitor in the body. It is synthesized primarily in the liver in response to inflammation or injury and provides a nonspecific protection of the host [12e15]. Its concentrations in plasma vary between 1.5 and 3.5 mg/ml but may have a fourfold increase during inflammation [15]. It shows anti-inflammatory activity in vitro unrelated to protease inhibition [16]. AAT may also have antiatherogenic property via lowering vascular muscularization [17]. But its well-known function is inactivation and regulation of different proteinases particularly neutrophil elastase. This inactivation causes AAT to release a 4 kDa c-terminal protein sequence that has biological activities including making different cells like monocytes produce more LDL receptors. These receptors are then used for the clearance of LDL from plasma [18e20]. This fragment also interacts with CD36 scavenger receptor and causes monocytes to initiate their respiratory burst response [21]. Air pollution causes AAT to become oxidized in met358 and met351 residues via its oxidative effect. AAT uses methionine358 as bait; therefore, oxidation happens in the protein active site leading to its loss of function on elastase [12,13,22e24]. In the same way, elastase may lose its cleaving activity on AAT, leading to the decreased efficiency of AAT c-terminal end cleavage. AAT inactivation must happen easily in the lungs because of their large surface in contact with air pollution.

Oxidized-AAT/LDL complex formation Studies have shown that LDL attaches oxidized AAT and forms a complex. This complex is proposed to promote atherosclerosis when taken by monocytes [25].

Elastase Elastase is a powerful serine proteinase released by particularly neutrophils which are attracted to the site of

Elastase upsets endothelium by proteolysing matrix proteins such as collagens, proteoglycan and fibronectin [12,29]. These proteins serve endothelium/substratum attachment [12,23]. Elastase also damages endothelium by its direct cytotoxic effect on endothelial cells [28,29]. Endothelial injury causes vascular permeability to increase in the process of inflammation [30].

Hypothesis The hypothesis here is that the air pollution affects the physiological aspects of the blood and initiates a pathological series in it which leads to the arterial damage and atherosclerosis. The sequences of the pathogenesis process are as follows.

Air pollution changes the normal AAT function in the blood Air pollution as a kind of inflammation raises the level of AAT in plasma. On the other hand, the oxidants produced in the lungs in response to exposure to air pollution cause AAT to become oxidized and inactivated. Here it is insisted that the air pollution causes the direct oxidation of AAT in the lumen of lung vessels, rather than in the arterial walls which is the main stream idea regarding atherosclerosis formation [4]. This inactivation may decrease the efficiency of AAT c-terminal end cleavage. But the level of c-terminal end concentration and its biological activities may remain consistent or even increase because of increased rate of AAT production due to the inflammatory property of air pollution. This protein portion enhances lipid uptake by monocytes through upregulating LDL receptors [18e20]. It also causes local respiratory burst in vascular monocytes and thereby enhancing atherosclerosis [21]. In the next step, oxidized AAT attaches LDL and forms a complex in the blood stream of lungs. This complex has to approach macrophages beyond the endothelial layer in order to cause atherosclerosis. But it may pass this barrier only with great difficulty [25]. However, the process of passing the endothelium is facilitated with the mediation of elastase (discussed later).

The air pollution raises the level of elastase in the body Elastase is a sensitive marker of cardiovascular diseases [27] and air pollution is a cause of this kind of diseases [7e10]. Therefore here it is reasoned that air pollution increases the level of elastase in the body. The explanation for this

Pathological changes in the blood phenomenon is that, 1) air pollution’s inflammatory response attracts neutrophils to the lungs. These cells then release elastase in there [12]. 2) AAT is inactivated owing to the air pollution and loses its inactivating power on elastase [12,13,22e24]. AAT inactivation happens in the lungs, at the same place and time that neutrophils release elastase. So AAT cannot inactivate elastase because of its own inactivation. The study which argues that elastase concentration increases in sputum in response to exposure to ozone [31] is in favor of this part of the hypothesis since it is likely that the same increase happens in the blood stream of lungs. Studies about the effects of cigarette smoke on the blood have also shown that this part of air pollution increases elastase concentration in the blood stream of individuals who are even passive smokers [32].

AAT/LDL complexes pass the arterial walls with the mediation of elastase Elastase promotes endothelial damage [23] and here it is predicted that this damage is to such extent that oxidizedAAT/LDL complexes could pass the endothelium and approach macrophages that take and degradate them four times more effectively than LDL alone [25]. These macrophages then change into foam cells. This prediction is in accordance with the studies that correlate both air pollution and elastase with vascular changes and cardiovascular morbidities [8,12,23,27,28, 33,34]. These studies have shown that the air pollution causes vascular changes which are known as common changes in the process of atherogenesis and as it is hypothesized in the previous section air pollution increases the level of elastase in the blood. This enzyme is capable of damaging blood vessels and is known to be a sensitive marker of CAD [27]. So here it is concluded that the link between air pollution and vascular changes is elastase and the link between elastase and atherosclerosis is the increase in endothelial permeability for atherogenic like AAT/LDL complexes. It has to be mentioned that oxidants which are increased in the lungs are also capable of directly damaging vessels but they are more confined to the lungs - the very first source of air pollution oxidation.

303 This part of the hypothesis explains why elastase is a sensitive marker of CAD. In fact, this enzyme has a critical role in the pathogenesis of atherosclerosis which is the underlying cause of CAD.

Air pollution changes the physiological property of LDL uptake and makes it an atherogenic molecule Air pollution’s oxidative and inflammatory properties causes LDL to become oxidized in the blood like AAT molecules [26]. Then oxidized LDL goes through intima in the same way as AAT/LDL complexes do. Oxidation of LDL leads to the loss of arterial macrophage recognition by the LDL receptor and a shift to recognition by the oxidized LDL receptor and scavenger receptors [35e37]. ‘‘This change in receptor recognition results in cellular uptake of lipids in such a way that is not regulated by the cholesterol content of the cell’’ [4] and hence atherosclerosis occurs. Fig. 1 summarizes the process of air pollution-borne atherosclerosis disclosed herein.

Predictions 1. If the pattern of heamodynamicly caused atherosclerosis in the body is not considered - in people with no systemic inflammation but live in megacities - this disease follows a pattern of decreased gradient centrifugally from the lungs to farther tissues. This is because the source of oxidation is the lungs and the atherogenic molecules formed there attach the nearby vessels and hence the concentration of these molecules decreases as blood goes farther. The more polluted the air of an area and the healthier a person is, the more prominent this pattern is. This is a pattern of gradient atherosclerosis or aging of vessels which explains why coronary arteries are amongst those arteries highly susceptible to atherosclerosis (Because they are near the lungs.) 2. The herein proposed hypothesis also predicts immunity alterations in people living in air polluted areas since elastase directly kills the pathogen by attacking and lysing its membrane [12]. AAT also has antibacterial effects [38]. But in case of air pollution, AAT is both

Figure 1 The machanism of air pollution-borne atherosclerosis. 1. AAT becomes oxidized because of the oxidative property of the air pollution. 2. LDL attaches Ox.AAT and forms the atherogenic complex of Ox.AAT/LDL. 3. LDL is oxidized as a result of exposure to polluted air. 4. Elastase - which is produced in the blood by neutrophils or polymorphonuclear cells (PMNs)-damages the endothelium and the intima and thereby creating holes for Ox.AAT/LDL complexes to pass. 5. Macrophages take and degradate Ox.AAT/LDL complexes and change into foamy cells which results in the formation of atherosclerotic plaques.

304 increased in concentration and inactivated. So the cumulative effect of these two phenomena on bacterial infections is not clear and is yet to be studied. 3. The females are more susceptible to the air pollutionborne atherosclerosis. This is because the estrogen hormone has the capacity to enhance the AAT concentration in plasma [39]. Therefore the substrate for the herein disclosed process is supplied more and the process can progress more in females than males. On the other hand it can be predicted that AAT deficient patients must be more resistant to this disease.

M. Rismanchi

[4]

[5] [6] [7] [8]

Clinical implications This hypothesis proposes a mechanism for air pollutionborne atherosclerosis that can be disrupted in any of its stages. To avoid atherosclerosis in such a case these measures can be taken: 1. Lowering the level of elastase in plasma by heightening antielastase compounds in the body or by making antielastase antibodies via vaccination. 2. Placing antielastase antibody encoded tubes or the same devices such as stents in the lumen of pulmonary veins in order to decrease the level of elastase reaching coronary arteries. 3. Vaccination against the three dimensional structure found in the place of oxidized met358 residue in AAT in order to disrupt AAT/LDL-complex formation. The same antibody has already been produced in the form of monoclonal antibody for research [25]. This hypothesis can be tested by measuring the amount of oxidized-AAT/LDL complex passage through arterial walls which have been changed by elastase treatment. In order to measure this criterion, oxidized AAT monoclonal antibodies can be used [25].

[9]

[10]

[11] [12]

[13]

[14]

[15] [16]

[17]

[18]

Conflict of interest The author has no conflict of interest.

[19]

Acknowledgement

[20]

I would like to express my deep gratitude to Dr. Mehboodi for his careful editing of this article and Dr. A Bazargani, Mr. H Azimi and Mr. A Naghshvar for their assistance. At last but not at least I thank my parents who encourage me to investigate and pursue further studies.

References [1] Kiechl Stefan, Willeit Johann. The natural course of atherosclerosis: part I: incidence and progression. Arterioscler Thromb Vasc Biol 1999;19:1484e90. [2] Junqueira Luiz Carlos, Carneiro Jose. Basic histology. 11th ed. New York: McGraw-Hill Publishing/Medical Publishing Division; 2005. [3] Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W, et al. A definition of advanced types of atherosclerotic

[21]

[22]

[23]

[24]

lesions and a histological classification of atherosclerosis. Circulation 1995;92:1355e74. Berliner Judith A, Navab Mohamad, Fogelman Alan M, Frank Joy S, Demer Linda L, Edwards Peter A, et al. Atherosclerosis: basic mechanisms: oxidation, inflammation, and genetics. Circulation 1995;91:2488e96. Berliner JA, Heinecke JW. The role of oxidized lipoproteins in atherogenesis. Free Radic Biol Med 1996;20:707e27. Steinberg D. Low density lipoprotein oxidation and its pathobiological significance. J Biol Chem 1997;272:20963e6. Ku ¨nzlia Nino, Tagerb Ira B. Air pollution: from lung to heart. Swiss Med Wkly: , 2005;135:697e702. Suwa T, Hogg JC, Quinlan KB, Ohgami A, Vincent R, van Eeden SF. Particulate air pollution induces progression of atherosclerosis. J Am Coll Cardiol 2002;39:935e42. Ku ¨nzli N, Jerrett M, Mack WJ, Beckerman B, LaBree L, Gilliland F, et al. Ambient air pollution and atherosclerosis in Los Angeles. Environ Health Perspect 2005;113:201e6. Arden Pope III C, Dockery Douglas W. Health effects of fine particulate air pollution: lines that connect. A & WMA Crit Rev. Available from: 2006. Nel A. Atmosphere: enhanced: air pollution-related illness: effects of particles. Science 2005;308:804e6. McDowall Jennifer. Serpins, alpha 1-antitrypsin, ; March 19, 2007. Murray Robert K, Granner Daryl K, Rodwel Victor W. Harper’s illustrated biochemistry. 27th ed. Boston: McGraw-Hill publishing; 2006. p. 590, 591, 597. Molmenti EP, Perlmutter DH, Rubin DC. Cell-specific expression of alpha1-antitrypsin in human intestinal epithelium. J Clin Invest 92:2022e34. Shapiro L, Pott GB, Ralston AH. Alpha-1-antitrypsin inhibits human immunodeficiency virus type 1. FASEB J 15:115e22. Janciauskiene S, Larsson S, Larsson P, Virtala R, Jansson L, Stevens T. Inhibition of lipopolysaccharide-mediated human monocyte activation, in vitro, by alpha1-antitrypsin. Biochem Biophys Res Commun 2004 Aug 27;321(3):592e600. Wright JL, Farmer SG, Churg A. A neutrophil elastase inhibitor reduces cigarette smoke-induced remodelling of lung vessels. Eur Respir J 2003;22:77e81. Janciauskiene S, al Rayyes O, Floren CH, Eriksson S. Low density lipoprotein catabolism is enhanced by the cleaved form of alpha-1-antitrypsin. Scand J Clin Lab Invest 1997;57: 325e35. Janciauskiene S, Lindgren S. Effects of fibrillar C-terminal fragment of cleaved alpha1-antitrypsin on cholesterol homeostasis in HepG2 cells. Hepatology 1999;29:434e42. Janciauskiene S, Wright HT, Lindgren S. Atherogenic properties of human monocytes induced by the carboxyl terminal proteolytic fragment of alpha-1-antitrypsin. Atherosclerosis 1999;147:263e75. Janciauskiene S, Moraga F, Lindgren S. C-terminal fragment of alpha1-antitrypsin activates human monocytes to a proinflammatory state through interactions with the CD36 scavenger receptor and LDL receptor. Atherosclerosis 2001 Sep; 158(1):41e51. PMID: 11500173. Richardson DE, Regino CA, Yao H, Johnson JV. Methionine oxidation by peroxymonocarbonate, a reactive oxygen species formed from CO2/bicarbonate and hydrogen peroxide. Free Radic Biol Med 2003 Dec 15;35(12):1538e50. PMID: 14680677. Vercellotti G, Stroncek D, Jacob HS. Granulocyte oxygen radicals as potential suppressors of hemopoiesis: potentiating roles of lactoferrin and elastase; inhibitory role of oxygen radical scavengers. Blood Cells 1987;13(1e2):199e206. PMID: 3311218. Schlick W. Etiology of chronic bronchitis. Wien Med Wochenschr 1986 Dec 31;136(23e24):610e3. PMID: 3645943.

Pathological changes in the blood [25] Mashiba S, Wada Y, Takeya M, Sugiyama A, Hamakubo T, Nakamura A, et al. In vivo complex formation of oxidized alpha1-antitrypsin and LDL. Arterioscler Thromb Vasc Biol 2001;21:1801e8. [26] RiazMemon A, Staprans Ilona, Noor Mustafa. Infection and inflammation induce LDL oxidation in vivo. Arterioscler Thromb Vasc Biol 2000;20:1536e42. [27] Kosar F, Varol E, Ayaz S, Kutuk E, Oguzhan A, Diker E. Plasma leukocyte elastase concentration and coronary artery disease. Angiology 1998 Mar;49(3):193e201. PMID: 9523542. [28] Bless NM, Smith D, Charlton J, Czermak BJ, Schmal H, Friedl HP, et al. Protective effects of an aptamer inhibitor of neutrophil elastase in lung inflammatory injury. Curr Biol 1997 Nov 1;7(11):877e80. PMID: 9382799. [29] Saunders WB, Bayless KJ, Davis GE. MMP-1 activation by serine proteases and MMP-10 induces human capillary tubular network collapse and regression in 3D collagen matrices. J Cell Sci 2005 May 15;118(Pt 10):2325e40. PMID: 15870107. [30] Kumar, Abbas, Fausto, Mitchell. Robins basic pathology. 8th ed. 2007. [31] Hiltermann JT, Lapperre TS, van Bree L, Steerenberg PA, Brahim JJ, Sont JK, et al. Ozone-induced inflammation assessed in sputum and bronchial lavage fluid from asthmatics: a new noninvasive tool in epidemiologic studies on air pollution and asthma. Free Radic Biol Med 1999 Dec;27(11e 12):1448e54. PMID: 10641740.

305 [32] Du BY. The effects of passive smoking on health. Beijing Red Cross Chao Yang Hospital. Zhonghua Jie He He Hu Xi Za Zhi 1991 Apr;14(2):76e8. p. 126, PMID: 1879020. [33] Committee of the Environmental and Occupational Health Assembly of the American Thoracic Society. Health effects of outdoor air pollution. Am J Respir Crit Care Med 1996; 153:3e50. [34] Nemmar A, Hoylaerts MF, Nemery B. Effects of particulate air pollution on hemostasis. Clin Occup Environ Med 2006;5(4): 865e81. PMID: 17110297. [35] Brown MS, Goldstein JL. Scavenging for receptors. Nature 1990;343:508e9. [36] Plu ¨ddemann A, Neyen C, Gordon S. Macrophage scavenger receptors and host-derived ligands. Methods. 2007 Nov;43(3): 207e17. [37] Sparrow CP, Parthasarathy S, Steinberg D. A macrophage receptor that recognizes oxidized low density lipoprotein but not acetylated low density lipoprotein. J Biol Chem 1989;264: 2599e604. [38] Knappstein Sabine, Ide Tina, Schmidt M Alexander, Heusipp Gerhard. Alpha1-antitrypsin binds to and interferes with functionality of EspB from atypical and typical enteropathogenic Escherichia coli strains. Infect Immun Aug 2004; 72(8):4344e50. [39] Burtis CA, Ashwood ER, Bruns DE. Tietz textbook of clinical chemistry and molecular diagnosis. [chapter 20].