Pathology International

1996

DOI: 10.1111/j.1440-1827.1996.tb03552.x

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Both acute phase and constitutive serum amyloid A are present in atherosclerotic lesions

Toshiyuki Yamada

¹

,

Toshio Kakihara

²

,

Tomoko Kamishima

³

et al.

Abstract: The polymorphic protein, serum amyloid A (SAA), consists of acute phase isotypes and a constitutive isotype. Both are associated mostly with high density lipoproteins (HDL) in the circulation. In the present study, both SAA isotypes were detected by immunohistochemistry and immunoblotting using monoclonal antibodies in atherosclerotic lesions. As the distribution of SAA was identical with that of apolipoprotein B and SAA is known to be associated also with low density lipoproteins (LDL), SAA may also be delive… Show more

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Cited by 56 publications

(43 citation statements)

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“…Although most SAA is produced by the liver, SAA1, SAA2, and SAA4 also can be produced by extrahepatic sources (78). It is of interest that mRNA for SAA has been detected in all of the major cell types present in atherosclerotic lesions (78), which contain both acute-phase and constitutive forms of SAA protein (79).…”

Section: Saamentioning

confidence: 99%

Thematic review series: The Immune System and Atherogenesis. Lipoprotein-associated inflammatory proteins: markers or mediators of cardiovascular disease?

¹

,

²

,

³

2005

Journal of Lipid Research

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In humans, a chronically increased circulating level of C-reactive protein (CRP), a positive acute-phase reactant, is an independent risk factor for cardiovascular disease. This observation has led to considerable interest in the role of inflammatory proteins in atherosclerosis. In this review, after discussing CRP, we focus on the potential role in the pathogenesis of human vascular disease of inflammation-induced proteins that are carried by lipoproteins. Serum amyloid A (SAA) is transported predominantly on HDL, and levels of this protein increase markedly during acute and chronic inflammation in both animals and humans. Increased SAA levels predict the risk of cardiovascular disease in humans. Recent animal studies support the proposal that SAA plays a role in atherogenesis. Evidence is accruing that secretory phospholipase A 2 , an HDL-associated protein, and platelet-activating factor acetylhydrolase, a protein associated predominantly with LDL in humans and HDL in mice, might also play roles both as markers and mediators of human atherosclerosis. In contrast to positive acute-phase proteins, which increase in abundance during inflammation, negative acutephase proteins have received less attention. Apolipoprotein A-I (apoA-I), the major apolipoprotein of HDL, decreases during inflammation. Recent studies also indicate that HDL is oxidized by myeloperoxidase in patients with established atherosclerosis. These alterations may limit the ability of apoA-I to participate in reverse cholesterol transport. Paraoxonase-1 (PON1), another HDL-associated protein, also decreases during inflammation. PON1 is atheroprotective in animal models of hypercholesterolemia. Controversy over its utility as a marker of human atherosclerosis may reflect the fact that enzyme activity rather than blood level (or genotype) is the major determinant of cardiovascular risk. Thus, multiple lipoprotein-associated proteins that change in concentration during acute and chronic inflammation may serve as markers of cardiovascular disease. In future studies, it will be important to determine whether these proteins play a causal role in atherogenesis.

“…Although most SAA is produced by the liver, SAA1, SAA2, and SAA4 also can be produced by extrahepatic sources (78). It is of interest that mRNA for SAA has been detected in all of the major cell types present in atherosclerotic lesions (78), which contain both acute-phase and constitutive forms of SAA protein (79).…”

Section: Saamentioning

confidence: 99%

Thematic review series: The Immune System and Atherogenesis. Lipoprotein-associated inflammatory proteins: markers or mediators of cardiovascular disease?

¹

,

²

,

³

2005

Journal of Lipid Research

View full text Add to dashboard Cite

In humans, a chronically increased circulating level of C-reactive protein (CRP), a positive acute-phase reactant, is an independent risk factor for cardiovascular disease. This observation has led to considerable interest in the role of inflammatory proteins in atherosclerosis. In this review, after discussing CRP, we focus on the potential role in the pathogenesis of human vascular disease of inflammation-induced proteins that are carried by lipoproteins. Serum amyloid A (SAA) is transported predominantly on HDL, and levels of this protein increase markedly during acute and chronic inflammation in both animals and humans. Increased SAA levels predict the risk of cardiovascular disease in humans. Recent animal studies support the proposal that SAA plays a role in atherogenesis. Evidence is accruing that secretory phospholipase A 2 , an HDL-associated protein, and platelet-activating factor acetylhydrolase, a protein associated predominantly with LDL in humans and HDL in mice, might also play roles both as markers and mediators of human atherosclerosis. In contrast to positive acute-phase proteins, which increase in abundance during inflammation, negative acutephase proteins have received less attention. Apolipoprotein A-I (apoA-I), the major apolipoprotein of HDL, decreases during inflammation. Recent studies also indicate that HDL is oxidized by myeloperoxidase in patients with established atherosclerosis. These alterations may limit the ability of apoA-I to participate in reverse cholesterol transport. Paraoxonase-1 (PON1), another HDL-associated protein, also decreases during inflammation. PON1 is atheroprotective in animal models of hypercholesterolemia. Controversy over its utility as a marker of human atherosclerosis may reflect the fact that enzyme activity rather than blood level (or genotype) is the major determinant of cardiovascular risk. Thus, multiple lipoprotein-associated proteins that change in concentration during acute and chronic inflammation may serve as markers of cardiovascular disease. In future studies, it will be important to determine whether these proteins play a causal role in atherogenesis.

“…Endothelial cells in atherosclerotic lesions of human coronary and carotid arteries have been found to express SAA mRNA, in addition to other cells such as smooth muscle cells, macrophagederived "foam cells," adventitial macrophages, and adipocytes (10). SAA has also been found to be present in atherosclerotic plaques (11), and was locally increased at the site of ruptured plaques in acute myocardial infarction in comparison to CRP (12). These findings enhance the postulation that SAA is involved in atherogenesis, atherosclerosis and thrombogenesis.…”

mentioning

confidence: 99%

Serum Amyloid A Activation of Inflammatory and Adhesion Molecules in Human Coronary Artery and Umbilical Vein Endothelial Cells

¹

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²

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³

et al. 2007

Eur J Inflamm

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Inflammation is considered to be the driving force leading to atherogenic and atherosclerotic mechanisms. Increased levels of SAA predict the risk of coronary artery disease and even mortality from cardiovascular disease in humans. Recent animal and human studies have indicated that SAA plays a causal role in atherogenesis, although it is largely unclear how this occurs. The objectives of this study are to understand the role of SAA in activating possible atherogenic inflammatory responses in human coronary artery endothelial cells (HCAEC) and to compare them with human umbilical vein endothelial cells (HUVEC). Our hypothesis is that vein and artery endothelial cells have different expression patterns and levels, leading to differential inflammatory responses. HUVEC and HCAEC were grown in order to analyze the effects of SAA on endothelial expression of pro-inflammatory cytokines, such as IL-6, chemokines, such as IL-8, and adhesion molecules (s-ICAM, s-VCAM, E-selectin) by reverse transcription-PCR and ELISAs. We compared the dose responses of SAA between HUVEC and HCAEC. SAA activated both HUVEC and HCAEC pro-inflammatory factors in a dose-dependent manner. In comparison however, HCAEC showed a strikingly greater sensitivity to SAA, with a higher level of expression of all pro-inflammatory markers at much lower concentrations of SAA, and their much greater stimulation at higher SAA concentrations. SAA also generated a dose-dependent positive feedback response on its own mRNA expression in HCAEC as compared to HUVEC. In summary, there are distinct significant differences in the levels of inflammatory markers and adhesion molecules between HUVEC and HCAEC SAA induced dose responses that could potentially account for HCAEC greater susceptibility to inflammation and atherogenesis.Inflammation is known to be a major driving force in atherogenesis and in the initiation of coronary plaque formation (l). Cohort studies have reported that acute inflammatory parameters [such as C-reactive protein (CRP) or serum amyloid A (SAA)], cellular adhesion molecules, cytokines and chemokines are all elevated among patients at risk for future coronary occlusion (2-4). Increased SAA levels predict the risk of coronary artery disease in humans (5) and multivariate studies have identified SAA as an independent predictor of mortality in acute myocardial infarction patients (6). Recent animal and human studies indicate that SAA plays a causal role in atherogenesis (7), however it is largely unclear how the induced SAA play this role.The endothelium is heterogeneous due to its

“…Production of APP by the liver is induced by proinflammatory cytokines, such as interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-␣), and IL-6, which are released by host cells in response to microbial stimuli (2,61). Localized cellular production of APP, such as serum amyloid A (SAA), at sites of tissue injury has also been documented (38,74). Whereas substantial increases in APP levels occur during acute infection, systemic levels of these molecules appear to return to baseline or near-baseline levels during chronic processes in the host (2).…”

mentioning

confidence: 99%

Systemic Inflammation in Cardiovascular and Periodontal Disease: Comparative Study

³

et al. 2002

Clin Vaccine Immunol

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Epidemiological studies have implicated periodontal disease (PD) as a risk factor for the development of cardiovascular disease (CVD). These studies addressed the premise that local infection may perturb the levels of systemic inflammatory mediators, thereby promoting mechanisms of atherosclerosis. Levels of inflammatory mediators in the sera of subjects with only PD, only CVD, both diseases, or neither condition were compared. Subjects were assessed for levels of C-reactive protein (CRP), serum amyloid A (SAA), ceruloplasmin, ␣ 1 -acid-glycoprotein (AAG), ␣ 1 -antichymotrypsin (ACT), and the soluble cellular adhesion molecules sICAM-1 and sVCAM by enzyme-linked immunoabsorbent and/or radial immunodiffusion assays. CRP levels in subjects with either condition alone were elevated twofold above subjects with neither disease, whereas a threefold increase was noted in subjects with both diseases (P ‫؍‬ 0.0389). Statistically significant increases in SAA and ACT were noted in subjects with both conditions compared to those with one or neither condition (P ‫؍‬ 0.0162 and 0.0408, respectively). Ceruloplasmin levels were increased in subjects with only CVD (P ‫؍‬ 0.0001). Increases in sVCAM levels were noted in all subjects with CVD (P ‫؍‬ 0.0054). No differences in sICAM levels were noted among subject groups. A trend toward higher levels of AAG was noted in subjects with both conditions and for ACT in subjects with only PD. Immunohistochemical examination of endarterectomy specimens of carotid arteries from subjects with atherosclerosis documented SAA and CRP deposition in association with atheromatous lesions. The data support the hypothesis that localized persistent infection may influence systemic levels of inflammatory mediators. Changes in inflammatory mediator levels potentially impact inflammation-associated atherosclerotic processes.Hypercholesterolemia, lipid metabolism imbalances, hypertension, age, gender, body mass index, diabetes mellitus, homocysteine, stress, and smoking are widely accepted as "classic" risk factors for development of cardiovascular disease (CVD). However, it has also become clear that the contribution of these factors cannot be supported in 25 to 50% of subjects who develop CVD and cerebrovascular disease (39, 53). These observations have intensified initiatives to identify additional risk factors for the development of atherosclerosis and vascular ischemic diseases. Recent evidence indicates that the development of CVD correlates with elevated levels of C-reactive protein (CRP) (25,30,35,45,54,55) and soluble cellular adhesion molecules (CAM) (27,48,56,76) which are produced in response to cellular damage. These observations have led to a reexamination of one of the earliest theories regarding the etiology of atherosclerosis and coronary heart disease (CHD): inflammatory processes which may arise in association with infection (39, 42).In the mid-1800s, Virchow drew attention to the presence of two distinct lesions along arterial vessel walls: the classical "fatty streak" and a second ...

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