This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kugiyama, K. Articles by Yasue, H. Search for Related Content PubMed PubMed Citation Articles by Kugiyama, K. Articles by Yasue, H. Related Collections Lipids Pathophysiology Risk Factors Chronic ischemic heart disease Lipid and lipoprotein metabolism

(Circulation. 1999;100:1280-1284.)
© 1999 American Heart Association, Inc.

Clinical Investigation and Reports

Circulating Levels of Secretory Type II Phospholipase A₂ Predict Coronary Events in Patients with Coronary Artery Disease

Kiyotaka Kugiyama, MD; Yasutaka Ota, MD; Keiji Takazoe, MD; Yasushi Moriyama, MD; Hiroaki Kawano, MD; Yuji Miyao, MD; Tomohiro Sakamoto, MD; Hirofumi Soejima, MD; Hisao Ogawa, MD; Hideki Doi, MD; Seigo Sugiyama, MD; Hirofumi Yasue, MD

From the Department of Cardiovascular Medicine, Kumamoto University School of Medicine, Kumamoto, Japan.

Correspondence to Kiyotaka Kugiyama, MD, PhD, Department of Cardiovascular Medicine, Kumamoto University School of Medicine, Honjo 1-1-1, Kumamoto City, Japan 860-8556. E-mail kiyo{at}gpo.kumamoto-u.ac.jp

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background—The circulating levels of secretory nonpancreatic type II phospholipase A₂ (sPLA₂) are increased in various chronic inflammatory diseases and the increase in the levels correlates with the disease severity. sPLA₂ may possibly play a role in atherogenesis and is highly expressed in atherosclerotic arterial walls that are known to have inflammatory features. Thus, this study prospectively examined whether circulating levels of sPLA₂ may have a significant risk and prognostic values in patients with coronary artery disease (CAD).

Methods and Results—Plasma levels of sPLA₂ were measured in 142 patients with CAD and in 93 control subjects by a radioimmunoassay. The sPLA₂ levels had a significant and positive relations with serum levels of C-reactive protein, a marker of systemic inflammation, and with the number of the traditional coronary risk factors associated with individuals. Multivariate logistic regression analysis showed that higher levels of sPLA₂ (>246 ng/dL; 75th percentile of sPLA₂ distribution in controls) were a significant and independent risk factor for the presence of CAD. In multivariate Cox hazard analysis, the higher levels of sPLA₂ were a significant predictor of developing coronary events (ie, coronary revascularization, myocardial infarction, coronary death) during a 2-year follow-up period in patients with CAD independent of other risk factors, including CRP levels, an established inflammatory predictor.

Conclusions—The increase in circulating levels of sPLA₂ is a significant risk factor for the presence of CAD and predicts clinical coronary events independent of other risk factors in patients with CAD; these results may reflect possible relation of sPLA₂ levels with inflammatory activity in atherosclerotic arteries.

Key Words: atherosclerosis • coronary disease • lipids • prognosis • risk factors

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Phospholipases A₂ (PLA₂) are ubiquitous enzymes that hydrolyze the sn-2-acyl bond of phospholipids of cell membrane and lipoproteins and yield free fatty acids and lysophospholipids, precursors of various proinflammatory lipid mediators including leukotrienes, eicosanoids, prostaglandins, and platelet-activating factors.^{1 2 3} Several studies showed that secretory nonpancreatic type II phospholipase A₂ (sPLA₂) might importantly contribute to the pathogenesis of various inflammatory diseases.^{2 3} Recently, sPLA₂ was found to be highly expressed in human atherosclerotic arterial walls,^{4 5 6} where the inflammatory process is known to have a pathogenetic role.^{7 8 9} The lipid products generated through sPLA₂ and their related products, including modified LDLs, participate in the development of atherosclerosis and play a significant role in the pathogenesis of coronary artery disease (CAD).^{8 9 10 11 12} There is growing evidence^{2 3 13 14} that the circulating levels of sPLA₂ are increased in various inflammatory diseases and that the levels reflect severity of these diseases, including rheumatic arthritis, inflammatory bowel diseases, and sepsis. Thus, it is expected that the circulating levels of sPLA₂ may also be increased in patients with CAD. In this study, we prospectively examined whether the circulating levels of sPLA₂ may have a significant risk and prognostic values in patients with CAD.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Study Patients
This study enrolled 196 consecutive patients with CAD who underwent elective and diagnostic cardiac catheterization for chest pain or ischemic changes in ECG in Kumamoto University Hospital. The patients with CAD who were admitted for the planned revascularization therapy were not eligible for this study. All patients had angiographic documentation of organic stenosis of >70% of at least one major coronary artery. Forty-nine patients were excluded because they had one of the following exclusion criteria: myocardial infarction, major surgery and trauma, and serious infectious diseases within previous 4 weeks; malignancies; and chronic inflammatory diseases, including rheumatoid arthritis, osteoarthritis, and inflammatory bowel disease. Ultimately, 147 (75%) of the 196 patients were included in this study. Patients' characteristics are shown in Table 1.

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics of Study Patients and Controls

This study also enrolled 124 consecutive control subjects who underwent cardiac catheterization for atypical chest pain during the same study period as the patients with CAD. These control subjects were studied to evaluate sPLA₂ as a risk factor differing between patients with CAD and non-CAD patients. The control subjects had angiographically normal coronary arteries (<10% stenosis), normal left ventriculography, and no clinical evidence of coronary artery spasm and syndrome X. Of these subjects, this study finally included 93 age- and sex-matched control subjects who did not have any of the same exclusion criteria as described above for the patients with CAD. Written informed consent was obtained from all patients and subjects before the study. This study was in agreement with the guidelines approved by the ethics committee at our institution.

Biochemical Measurements
Venous blood was taken from all of the study patients and control subjects after an overnight fast. Blood samples, anticoagulated with EDTA or citrate, were immediately centrifuged at 3000 rpm at 4°C for 10 minutes. The plasma was aliquoted and stored at -80°C until analyzed. Levels of immunoreactive sPLA₂ in EDTA-plasma were measured by a radioimmunoassay using a monoclonal antibody developed against membrane-associated PLA₂, which was purified from human spleen and was identical with type IIA PLA₂ purified from rheumatoid arthritic synovial fluid (Shionogi Pharmaceutical Ltd., Osaka, Japan).^{15 16} This monoclonal antibody had no detectable cross-reactivity with human pancreatic PLA₂ (type IB).^{14 15} The radioimmunoassay gave a linear response in a range from 78 to 5000 ng/dL of sPLA₂.^{14 15} The interassay and intra-assay coefficients of variation were <8%.^{14 15} The plasma levels of the immunoreactive sPLA₂ had a significant correlation with the calcium-dependent PLA₂ activity in the citrated plasma (=0.923, P<0.0001, n=88 by Spearman's rank correlation test), a result which is compatible with that in previous reports.^{13 14} Serum levels of C-reactive protein (CRP) were measured in all of the control subjects and the patients with CAD using an N Latex CRP immunodetection kit (Dade Behring).^{14 15} Serum levels of total cholesterol, triglycerides, and HDL-cholesterol were measured by the enzymatic methods,¹⁷ and LDL-cholesterol levels were calculated as previously described.¹⁷

Follow-Up Study
After laboratory samples and catheterization data were obtained, the 147 patients with CAD (1-vessel disease, 70 patients; 2-vessel disease, 34 patients; three-vessel disease, 27 patients; left main coronary stenosis, 16 patients) were followed up every month in hospital or with a clinic visit for a maximum of 24 months or until occurrence of one of the following clinical coronary events: recurrent or refractory angina pectoris requiring coronary revascularization by PTCA or CABG, nonfatal myocardial infarction, and cardiac death. Time from the day when blood sampling was performed to first coronary event was prospectively evaluated. Diagnosis of myocardial infarction was made by chest pain, appearance of new Q wave on the ECG, and elevation of creatine kinase enzyme to more than twice the upper limit of normal. Cause of death was determined from hospital records. For the study, revascularization therapy based only on angiographic data were not counted as a coronary event. All of the patients received standardized medical therapy. The patients with high extent of CAD (3-vessel disease or left main coronary stenosis) who were included in this study were also followed up without revascularization therapy immediately after the inclusion because of diffuse peripheral CAD, a high risk with the procedure, previous CABG or repeated PTCA, or unwillingness for the revascularization therapy. The attending physician and interventional cardiologists independent of this prospective study decided the need for and timing of revascularization.

Statistical Analysis
Because sPLA₂ levels were not distributed normally, results of sPLA₂ levels are expressed as median and range (25th and 75th percentiles) and nonparametric analyses were used. Mann-Whitney U test was used to evaluate difference in sPLA₂ levels between the 2 groups. Spearman's rank correlation test was used for relations of sPLA₂ levels with CRP levels and number of the coronary risk factors associated with individuals. To evaluate sPLA₂ levels as an independent risk factor differing between the patients with CAD and the control subjects, forward, stepwise, multiple logistic regression analysis was performed using the following factors as categorical covariates: smoking history (defined as smoking at least 10 cigarettes per day for 10 years), hypertension (140/90 mm Hg or requiring antihypertensive medication), diabetes mellitus (according to World Health Organization criteria,¹⁸ hypercholesterolemia (220 mg/dL or the use of lipid-lowering medications), high LDL-cholesterol (130 mg/dL), low HDL-cholesterol (<35 mg/dL), and high CRP levels (>0.48 mg/dL, 90th percentile of the distribution of the CRP levels in the control subjects). Kaplan-Meier method (log-rank test) was applied in survival analysis according to the levels of sPLA₂. The predictive value for coronary events during the follow-up period was assessed by Cox proportional hazard analysis. The multivariate Cox analysis always included the following factors as categorical covariates: sPLA₂ levels, stenosis of the left main coronary artery, number of coronary arteries with stenosis, low left ventricular ejection fraction (LVEF) on baseline left ventriculography (< 50%), age (70 years), sex (male), smoking history, hypertension, diabetes mellitus, hypercholesterolemia, high LDL-cholesterol, and low HDL-cholesterol. Cutoff point (246 ng/dL) between higher and lower levels of sPLA₂ was arbitrarily defined as 75th percentile of the distribution of the sPLA₂ levels in the control subjects. In Cox hazard model and Kaplan-Meier analyses, sPLA₂ levels were divided into tertiles that were based on 90th and 75th percentiles of the distribution of the sPLA₂ levels in the control subjects. On scoring the number of coronary arteries with stenosis, stenosis of the left main coronary artery was counted as 2-vessel disease. Mean values of continuous variables with normal distribution and frequencies among subgroups were compared by unpaired t test and ² analysis, respectively. Statistical significance was defined as P<0.05. The analyses were performed partly using SPSS Professional Statistics 6.1 for the Macintosh (SPSS Japan Inc).

	Results

Top Abstract Introduction Methods Results Discussion References

 
sPLA₂ as a Coronary Risk Factor
The distribution of the levels of sPLA₂ immunoreactivity in patients with CAD was skewed and shifted to lower levels with a median level of 286 (218 and 386) ng/dL, which was significantly higher than that in control subjects (191 [154 and 246] ng/dL) (P<0.0001). The levels of sPLA₂ had a significant and positive correlation with CRP levels (Figure 1). As shown in Figure 2, the levels of sPLA₂ were significantly related with the number of the traditional coronary risk factors associated with individuals. There was no significant association of higher sPLA₂ levels (>246 ng/dL, 75th percentile of the sPLA₂ distribution in controls) with each of the traditional coronary risk factors (age 70 years, smoking history, diabetes mellitus, hypertension, hypercholesterolemia, and low HDL-cholesterol).

View larger version (21K): [in this window] [in a new window]   Figure 1. Relation between levels of sPLA2 and C-reactive protein in patients with CAD.

View larger version (21K): [in this window] [in a new window]   Figure 2. Box and whisker plots showing relation between sPLA2 levels and the number of the traditional coronary risk factors associated with individuals, including age (70 years), histories of smoking, diabetes mellitus, hypertension, hypercholesterolemia (220 mg/dL), and low HDL-cholesterol (<35 mg/dL) in patients with CAD and control subjects. Lines within boxes represent median values; upper and lower lines of boxes, 75th and 25th percentiles, respectively; upper and lower bars outside of boxes, 90th and 10th percentiles, respectively. n=27 in 0 coronary risk factor, 62 in 1 risk, 65 in 2 risks, 51 in 3 risks, and 30 in 4 risks.

The patients with CAD had significantly lower HDL-cholesterol levels, higher LDL-cholesterol levels, higher CRP levels, higher rates of diabetes mellitus and hypertension, and higher sPLA₂ levels compared to control subjects (Table 1). In multiple logistic regression analysis with forward stepwise selection, the higher levels of sPLA₂ (>246 ng/dL), diabetes mellitus, and hypertension were the variables differing significantly and independently between the patients with CAD and the control subjects, as shown in Table 2. The sPLA₂ levels were significantly higher in patients with unstable angina (the class B of Braunwald's classification) than stable angina (median [25th and 75th percentiles], 309 ng/dL [243, 461] versus 268 ng/dL,[217, 338], n= 34 and 108, respectively; P=0.03). The sPLA₂ levels were higher in patients with peripheral artery disease (diagnosed by angiography) than those without it (median [25th, 75th], 377 ng/dL [311, 583] versus 279 ng/dL, [217, 365], n=10 and 132, respectively; P=0.02).

View this table: [in this window] [in a new window]   Table 2. Multiple Logistic Regression Analysis: Final Significant Variables Differing Between Patients with CAD and Control Subjects

sPLA₂ as a Predictor of Coronary Events in Patients with CAD
All of the patients received the standard medical therapy consisting of a combination of calcium channel blockers (used in 82% of patients), ß-blockers (41%), nitrates (70%), angiotensin-converting enzyme inhibitor (38%), aspirin (93%), and lipid-lowering drugs (34%) during the follow-up study. Seven patients with unstable angina and high extent of CAD had intravenous infusion of heparin and nitrates for several days (2 to 7 days) after the inclusion. Only 5 patients with CAD were lost to follow-up. The remaining 142 patients with CAD were followed for a mean duration of 17.2 months (range, 0.5 to 24 months). The patients with higher levels of sPLA₂ (>246 ng/dL, 95 patients) had 41 coronary events (14 PTCA, 13 CABG, 5 myocardial infarction, 9 coronary death) during the follow-up period, whereas the patients with lower levels (246 ng/dL, 47 patients) had 7 events (1 PTCA, 5 CABG, 1 coronary death) (P<0.01 in frequencies of coronary events between the 2 subgroups). There was no significant difference in the rates of each of the drugs used between the patients with and without coronary events during the follow-up period (data not shown). Kaplan-Meier analysis demonstrated a significantly higher probability of developing the clinical coronary events in the patients with the higher levels of sPLA₂ than those with the lowest levels, as shown in Figure 3. In univariate Cox proportional hazard model analysis, higher levels of sPLA₂ (Table 3), higher levels of CRP (>0.48 mg/dL, 90th percentile of the CRP distribution in controls) (Odds, 1.8; 95% CI, 1.1 to 3.3, P=0.04 as compared with lower CRP levels [0.48 mg/dL]), stenosis of the left main coronary artery (Odds, 2.3, 95% CI, 1.1 to 4.9, P=0.02), and 3-vessel disease (Odds, 2.0, 95% CI, 1.0 to 3.9, P=0.04, compared with 1-vessel disease) were a significant predictor of the clinical coronary events in patients with CAD. Multivariate Cox proportional hazard analysis showed that only higher levels of sPLA₂ were a significant predictor of the coronary events independent of the traditional risk factors, left main coronary stenosis, 3-vessel disease, and low LVEF (Table 3). When CRP was added to the covariates in multivariate Cox analysis, sPLA₂ but not CRP remained a significant predictor of the future coronary events independent of the other risk factors (Odds, 3.3; 95% CI, 1.3 to 9.2; P=0.01 highest versus lowest tertile of sPLA₂ levels; odds, 1.3; 95% CI; 0.67 to 2.6; P=0.43, higher versus lower CRP levels). The inclusion of previous myocardial infarction and unstable angina at baseline examination into the covariates in the multivariate Cox analysis did not significantly affect the predictive value of higher sPLA₂ levels (highest versus lowest tertile of sPLA₂ levels, after addition of previous myocardial infarction into the covariates: Odds, 3.5; 95% CI, 1.4 to 8.3; P=0.006, after addition of unstable angina into the covariates: odds, 3.3; 95% CI, 1.4 to 8.1; P=0.008). Previous myocardial infarction and revascularization therapy before inclusion in this study, presence of unstable angina at baseline examination, low LVEF, and other traditional coronary risk factors did not have significant predictive value for coronary events in the study patients with CAD in either univariate or multivariate Cox proportional hazard analysis.

View larger version (15K): [in this window] [in a new window]   Figure 3. Kaplan-Meier curves comparing the probability of developing coronary events according to the sPLA2 levels during follow-up period maximally for 24 months after enrollment in 142 patients with CAD. End points were revascularization (PTCA and CABG) due to recurrent and refractory angina pectoris, nonfatal myocardial infarction, and cardiac death. Time to first coronary event was prospectively evaluated. sPLA2 levels were divided into tertiles based on 90th and 75th percentiles (366 and 246 ng/dL, respectively) of the distribution of sPLA2 levels in control subjects. n=37, 58, and 47 in the highest (>366 ng/dL), the second (between 247 and 366 ng/dL), and the lowest (246 ng/dL) tertile, respectively.

View this table: [in this window] [in a new window]   Table 3. Cox Proportional Hazard Model Analysis of Risks of Developing Coronary Events According to the Levels of sPLA2 in Patients with CAD

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The study demonstrated that the increase in plasma levels of sPLA₂ was an independent risk factor for the presence of CAD and that the increase in the levels predicted the development of clinical coronary events in patients with CAD. There is increasing evidence that atherosclerosis is an inflammatory disease that develops in response to the coronary risk factors.^{7 8 9 12} In this context, the present study further showed that the circulating levels of sPLA₂ were significantly correlated with the levels of CRP, a marker of systemic inflammation, and with the number of the traditional coronary risk factors associated with individuals. These imply that the increase in sPLA₂ levels in patients with CAD may reflect the inflammatory activity in the development of atherosclerosis. sPLA₂ may be one of the inflammatory markers, but sPLA₂ is a better inflammatory predictor of coronary events than CRP, a well established inflammatory prognostic marker because sPLA₂ but not CRP remained a significant and independent predictor in the multivariate Cox hazard analysis when addition of both factors into the covariates.

sPLA₂ is shown to be induced in vascular cells by cytokines such as interleukin-1 and tumor necrosis factor-,^{2 3 19 20 21} which abundantly exist in atherosclerotic arterial walls and have crucial roles in the inflammatory and immunological features in atherosclerotic development.^{7 9 11} These cytokines could stimulate synthesis of sPLA₂ in the atherosclerotic arterial walls and release into circulation, resulting in the elevation of the sPLA₂ levels in patients with CAD.

The lipid products generated through PLA₂ and their related products, such as lysophosphatidylcholine and modified LDL, are proatherogenic and proinflammatory^{2 3 10 11} and they activate vascular cells to produce plasminogen activators (PA), PA inhibitor-1, adhesion molecules, various proatherogenic cytokines and growth factors, and oxygen free radicals,^{10 22 23 24} leading to atherothrombotic development and plaque instability in the atherosclerotic arterial walls.^{8 9 12 25} This atherothrombogenic role of sPLA₂ may result in the association of the increased levels of sPLA₂ with the high frequency of future coronary evens in patients with CAD, as observed in our study. The causative role of sPLA₂ levels in human plaque unstabilization is now under investigation in our laboratory.

Recent reports have demonstrated that the increase in levels of CRP was associated with CAD.^{26 27} CRP is hepatically derived and has an uncertain physiological role in atherosclerotic development and in CAD. sPLA₂ could be also one of acute phase reactants.^{2 3 14 15} However, unlike CRP, the lipid mediators produced through sPLA₂ and their related lipids in the arterial walls can stimulate T cells and macrophages to synthesize and release the proatherogenic and proinflammatory cytokines,^{2 3 7 8 9 10 11 28} which may in turn induce sPLA₂ production in the atherosclerotic arterial walls.^{2 3 19 20 21} These positive feedback mechanisms could amplify this sequence of events in the atherosclerotic arterial walls, thereby sPLA₂ present in the arterial walls may play an important role in the pathogenesis of CAD, not simply as a marker of inflammation.

This study showed that diabetes mellitus, hypertension, and high sPLA₂ levels were significant and independent variables differing between patients with CAD and the control subjects. However, in the present prospective study, only high sPLA₂ levels (but not other traditional coronary risk factors including diabetes and hypertension) had predictive values for coronary events. The lack of the predictive significance of diabetes and hypertension in the present prospective study may be partly explained by the modification of these traditional risk factors during the follow-up by medications and improvement of lifestyle. Our study also showed that extensive coronary diseases (left main coronary disease and 3-vessel disease) had weak but significant probability for clinical coronary events in the univariate analysis. However, presence of the extensive coronary diseases alone may not be related directly to the significant probability of coronary events, which will not necessarily be provoked at the sites of severe coronary stenosis on baseline angiograms.²⁵ Other associated risk factors may additionally contribute to the significant probability because the extensive coronary diseases did not remain significant in the multivariate analysis.

This study is limited by the small number of the studied patients. Also, a case-control study has cross-sectional nature and it may have inherent selection bias of cases and controls. A trial with specific inhibitors of sPLA₂ activity in a large number of study patients with homogeneous risk is required to assess the precise role of sPLA₂ in the pathogenesis of CAD.

In conclusion, high levels of sPLA₂ in the circulation have an independent risk factor for the presence of CAD and predict future coronary events in patients with CAD.

	Acknowledgments

 
This study was supported in part by grants-in-aid for C09670730 from the Ministry of Education, Science, and Culture and the ONO Medical Research Foundation, Osaka, Japan. We thank Professor Michio Ogawa, MD, PhD, Second Department of Surgery, Kumamoto University School of Medicine, for helpful discussion.

Received March 12, 1999; revision received June 10, 1999; accepted June 22, 1999.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Dennis EA. Diversity of group types, regulation, and function of phospholipase A₂. J Biol Chem. 1994;269:13057–13060.[Free Full Text]
   
2. Pruzanski W, Vadas P. Phospholipase A₂ - a mediator between proximal and distal effectors of inflammation. Immunol Today. 1991;12:143–146.[Medline] [Order article via Infotrieve]
   
3. Murakami M, Kudo I, Inoue K. Secretory phospholipase A₂. J Lipid Mediat Cell Signal. 1995;12:119–130.[Medline] [Order article via Infotrieve]
   
4. Menschikowski M, Kasper M, Lattke P, Schiering A, Schiefer S, Stockinger H, Jaross W. Secretory group II phospholipase A₂ in human atherosclerotic plaques. Atherosclerosis. 1995;118:173–181.[Medline] [Order article via Infotrieve]
   
5. Hurt-Camejo E, Andersen S, Standal R, Rosengren B, Sartipy P, Stadberg E, Johansen B. Localization of nonpancreatic secretory phospholipase A₂ in normal and atherosclerotic arteries: activity of the isolated enzyme on low- density lipoproteins. Arterioscler Thromb Vasc Biol. 1997;17:300–309.[Abstract/Free Full Text]
   
6. Elinder LS, Dumitrescu A, Larsson P, Hedin U, Frostegård J, Claesson HE. Expression of phospholipase A₂ isoforms in human normal and atherosclerotic arterial wall. Arterioscler Thromb Vasc Biol. 1997;17:2257–2263.[Abstract/Free Full Text]
   
7. Hansson GK, Jonasson L, Seifert PS, Stemme S. Immune mechanisms in atherosclerosis. Arteriosclerosis. 1989;9:567–578.[Abstract/Free Full Text]
   
8. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:801–809.[Medline] [Order article via Infotrieve]
   
9. Libby P. Molecular bases of the acute coronary syndromes. Circulation. 1995;91:2844–2850.[Free Full Text]
   
10. Witztum JL, Steinberg D. Role of oxidized low density lipoprotein in atherogenesis. J Clin Invest. 1991;88:1785–1792.
    
11. Hajjar DP, Pomerantz KB. Signal transduction in atherosclerosis: integration of cytokines and the eicosanoid network. FASEB J. 1992;6:2933–2941.[Abstract]
    
12. Selwyn AP, Kinlay S, Ganz P. Atherogenesis and ischemic heart disease. Am J Cardiol. 1997;80:3H–7H.[Medline] [Order article via Infotrieve]
    
13. Lin MKS, Farewell V, Vadas P, Bookman AA, Keystone EC, Pruzanski W. Secretory phospholipase A₂ as an index of disease activity in rheumatoid arthritis: prospective double blind study of 212 patients. J Rheumatol. 1996;23:1162–1166.[Medline] [Order article via Infotrieve]
    
14. Minami T, Tojo H, Shinomura Y, Tarui S, Okamoto M. Raised serum activity of phospholipase A₂ immunochemically related to group II enzyme in inflammatory bowel disease: its correlation with disease activity of Crohn's disease and ulcerative colitis. Gut. 1992;33:914–921.[Abstract/Free Full Text]
    
15. Matsuda Y, Ogawa M, Sakamoto K, Yamashita S, Kanda A, Kohno M, Yoshida N, Nishijima J, Murata A, Mori T. Development of a radioimmunoassay for human group-II phospholipase A₂ and demonstration of postoperative elevation. Enzyme. 1991;45:200–208.[Medline] [Order article via Infotrieve]
    
16. Kanda A, Ono T, Yoshida N, Tojo H, Okamoto M. The primary structure of a membrane-associated phospholipase A₂ from human spleen. Biochem Biophys Res Commun. 1989;163:42–48.[Medline] [Order article via Infotrieve]
    
17. Kugiyama K, Doi H, Motoyama T, Soejima H, Misumi K, Kawano H, Nakagawa O, Yoshimura M, Ogawa H, Matsumura T, Sugiyama S, Nakano T, Nakajima K, Yasue H. Association of remnant lipoprotein levels with impairment of endothelium-dependent vasomotor function in human coronary arteries. Circulation. 1998;97:2519–2526.[Abstract/Free Full Text]
    
18. The Expert Committee. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care.. 1997;20:1183–1197.[Medline] [Order article via Infotrieve]
    
19. Nakano T, Ohara O, Teraoka H, Arita H. Group II phospholipase A₂ mRNA synthesis is stimulated by two distinct mechanisms in rat vascular smooth muscle cells. FEBS Lett. 1990;261:171–174.[Medline] [Order article via Infotrieve]
    
20. Murakami M, Kudo I, Inoue K. Molecular nature of phospholipase A₂ involved in prostaglandin I₂ synthesis in human umbilical vein endothelial cells. J Biol Chem. 1993;268:839–844.[Abstract/Free Full Text]
    
21. Kuwata H, Nakatani Y, Murakami M, Kudo I. Cytosolic phospholipase A₂ is required for cytokine-induced expression of type IIA secretory phospholipase A₂ that mediates optimal cyclooxygenase-2-dependent delayed prostaglandin E₂ generation in rat 3Y1 fibroblasts. J Biol Chem. 1998;273:1733–1740.[Abstract/Free Full Text]
    
22. Kugiyama K, Sakamoto T, Misumi I, Sugiyama S, Ohgushi M, Ogawa H, Horiguchi M, Yasue H. Transferable lipids in oxidized low-density lipoprotein stimulate plasminogen activator inhibitor-1 and inhibit tissue- type plasminogen activator release from endothelial cells. Circ Res. 1993;73:335–343.[Abstract/Free Full Text]
    
23. Kume N, Gimbrone MA Jr. Lysophosphatidylcholine transcriptionally induces growth factor gene expression in cultured human endothelial cells. J Clin Invest. 1994;93:907–911.
    
24. Ohara Y, Peterson TE, Zheng B, Kuo JF, Harrison DG. Lysophosphatidylcholine increases vascular superoxide anion production via protein kinase C activation. Arterioscler Thromb. 1994;14:1007–1013.[Abstract/Free Full Text]
    
25. Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation. 1995;92:657–671.[Free Full Text]
    
26. Liuzzo G, Biasucci LM, Gallimore JR, Grillo RL, Rebuzzi AG, Pepys MB, Maseri A. The prognostic value of C-reactive protein and serum amyloid a protein in severe unstable angina. N Engl J Med. 1994;331:417–424.[Abstract/Free Full Text]
    
27. Berk BC, Weintraub WS, Alexander RW. Elevation of CRP in "active" CAD. Am J Cardiol. 1990;65:168–172.[Medline] [Order article via Infotrieve]
    
28. Asaoka Y, Yoshida K, Sasaki Y, Nishizuka Y, Murakami M, Kudo I, Inoue K. Possible role of mammalian secretory group II phospholipase A₂ in T-lymphocyte activation: implication in propagation of inflammatory reaction. Proc Natl Acad Sci U S A. 1993;90:716–719.[Abstract/Free Full Text]
    

This article has been cited by other articles:

				D. Divchev, C. Grothusen, M. Luchtefeld, M. Thoenes, F. Onono, R. Koch, H. Drexler, and B. Schieffer Impact of a combined treatment of angiotensin II type 1 receptor blockade and 3-hydroxy-3-methyl-glutaryl-CoA-reductase inhibition on secretory phospholipase A2-type IIA and low density lipoprotein oxidation in patients with coronary artery disease Eur. Heart J., June 18, 2008; (2008) ehn276v1. [Abstract] [Full Text] [PDF]

				D. Fujioka, Y. Saito, T. Kobayashi, T. Yano, H. Tezuka, Y. Ishimoto, N. Suzuki, Y. Yokota, T. Nakamura, J.-e. Obata, et al. Reduction in Myocardial Ischemia/Reperfusion Injury in Group X Secretory Phospholipase A2-Deficient Mice Circulation, June 10, 2008; 117(23): 2977 - 2985. [Abstract] [Full Text] [PDF]

				U. J. F. Tietge, N. Nijstad, R. Havinga, J. F. W. Baller, F. H. van der Sluijs, V. W. Bloks, T. Gautier, and F. Kuipers Secretory phospholipase A2 increases SR-BI-mediated selective uptake from HDL but not biliary cholesterol secretion J. Lipid Res., March 1, 2008; 49(3): 563 - 571. [Abstract] [Full Text] [PDF]

				N L A Misso, N Petrovic, C Grove, A Celenza, J Brooks-Wildhaber, and P J Thompson Plasma phospholipase A2 activity in patients with asthma: association with body mass index and cholesterol concentration Thorax, January 1, 2008; 63(1): 21 - 26. [Abstract] [Full Text] [PDF]

				P. T.E. Wootton, N. L. Arora, F. Drenos, S. R. Thompson, J. A. Cooper, J. W. Stephens, S. J. Hurel, E. Hurt-Camejo, O. Wiklund, S. E. Humphries, et al. Tagging SNP haplotype analysis of the secretory PLA2-V gene, PLA2G5, shows strong association with LDL and oxLDL levels, suggesting functional distinction from sPLA2-IIA: results from the UDACS study Hum. Mol. Genet., June 15, 2007; 16(12): 1437 - 1444. [Abstract] [Full Text] [PDF]

				Z. Mallat, J. Benessiano, T. Simon, S. Ederhy, C. Sebella-Arguelles, A. Cohen, V. Huart, N. J. Wareham, R. Luben, K.-T. Khaw, et al. Circulating Secretory Phospholipase A2 Activity and Risk of Incident Coronary Events in Healthy Men and Women: The EPIC-NORFOLK Study Arterioscler. Thromb. Vasc. Biol., May 1, 2007; 27(5): 1177 - 1183. [Abstract] [Full Text] [PDF]

				W. Koenig and N. Khuseyinova Biomarkers of Atherosclerotic Plaque Instability and Rupture Arterioscler. Thromb. Vasc. Biol., January 1, 2007; 27(1): 15 - 26. [Abstract] [Full Text] [PDF]

				F. C. de Beer and N. R. Webb Inflammation and atherosclerosis: Group IIa and Group V sPLA2 are not redundant. Arterioscler. Thromb. Vasc. Biol., July 1, 2006; 26(7): 1421 - 1422. [Full Text] [PDF]

				S. Levick, D. Loch, B. Rolfe, R. C. Reid, D. P. Fairlie, S. M. Taylor, and L. Brown Antifibrotic Activity of an Inhibitor of Group IIA Secretory Phospholipase A2 in Young Spontaneously Hypertensive Rats. J. Immunol., June 1, 2006; 176(11): 7000 - 7007. [Abstract] [Full Text] [PDF]

				A. Tedgui and Z. Mallat Cytokines in Atherosclerosis: Pathogenic and Regulatory Pathways Physiol Rev, April 1, 2006; 86(2): 515 - 581. [Abstract] [Full Text] [PDF]

				E. J. Armstrong, D. A. Morrow, and M. S. Sabatine Inflammatory Biomarkers in Acute Coronary Syndromes: Part III: Biomarkers of Oxidative Stress and Angiogenic Growth Factors Circulation, February 28, 2006; 113(8): e289 - e292. [Full Text] [PDF]

				P. T.E. Wootton, F. Drenos, J. A. Cooper, S. R. Thompson, J. W. Stephens, E. Hurt-Camejo, O. Wiklund, S. E. Humphries, and P. J. Talmud Tagging-SNP haplotype analysis of the secretory PLA2IIa gene PLA2G2A shows strong association with serum levels of sPLA2IIa: results from the UDACS study Hum. Mol. Genet., January 15, 2006; 15(2): 355 - 361. [Abstract] [Full Text] [PDF]

				Z. Mallat, Ph. G. Steg, J. Benessiano, M.-L. Tanguy, K. A. Fox, J.-P. Collet, O. H. Dabbous, P. Henry, K. F. Carruthers, A. Dauphin, et al. Circulating Secretory Phospholipase A2 Activity Predicts Recurrent Events in Patients With Severe Acute Coronary Syndromes J. Am. Coll. Cardiol., October 4, 2005; 46(7): 1249 - 1257. [Abstract] [Full Text] [PDF]

				U. J. F. Tietge, D. Pratico, T. Ding, C. D. Funk, R. B. Hildebrand, T. Van Berkel, and M. Van Eck Macrophage-specific expression of group IIA sPLA2 results in accelerated atherogenesis by increasing oxidative stress J. Lipid Res., August 1, 2005; 46(8): 1604 - 1614. [Abstract] [Full Text] [PDF]

				S. M. Boekholdt, T. T. Keller, N. J. Wareham, R. Luben, S. A. Bingham, N. E. Day, M. S. Sandhu, J. W. Jukema, J. J.P. Kastelein, C. E. Hack, et al. Serum Levels of Type II Secretory Phospholipase A2 and the Risk of Future Coronary Artery Disease in Apparently Healthy Men and Women: The EPIC-Norfolk Prospective Population Study Arterioscler. Thromb. Vasc. Biol., April 1, 2005; 25(4): 839 - 846. [Abstract] [Full Text] [PDF]

				A. Chait, C. Y. Han, J. F. Oram, and J. W. Heinecke Thematic review series: The Immune System and Atherogenesis. Lipoprotein-associated inflammatory proteins: markers or mediators of cardiovascular disease? J. Lipid Res., March 1, 2005; 46(3): 389 - 403. [Abstract] [Full Text] [PDF]

				L. Anderson Candidate-based proteomics in the search for biomarkers of cardiovascular disease J. Physiol., February 15, 2005; 563(1): 23 - 60. [Abstract] [Full Text] [PDF]

				M. F. Khalil, W. D. Wagner, and I. J. Goldberg Molecular Interactions Leading to Lipoprotein Retention and the Initiation of Atherosclerosis Arterioscler. Thromb. Vasc. Biol., December 1, 2004; 24(12): 2211 - 2218. [Abstract] [Full Text] [PDF]

				J. Oestvang, D. Bonnefont-Rousselot, E. Ninio, J. K. Hakala, B. Johansen, and M. W. Anthonsen Modification of LDL with human secretory phospholipase A2 or sphingomyelinase promotes its arachidonic acid-releasing propensity J. Lipid Res., May 1, 2004; 45(5): 831 - 838. [Abstract] [Full Text] [PDF]

				C. R. Wooton-Kee, B. B. Boyanovsky, M. S. Nasser, W. J.S. de Villiers, and N. R. Webb Group V sPLA2 Hydrolysis of Low-Density Lipoprotein Results in Spontaneous Particle Aggregation and Promotes Macrophage Foam Cell Formation Arterioscler. Thromb. Vasc. Biol., April 1, 2004; 24(4): 762 - 767. [Abstract] [Full Text] [PDF]

				K. Winkler, C. Abletshauser, I. Friedrich, M. M. Hoffmann, H. Wieland, and W. Marz Fluvastatin Slow-Release Lowers Platelet-Activating Factor Acetyl Hydrolase Activity: A Placebo-Controlled Trial in Patients with Type 2 Diabetes J. Clin. Endocrinol. Metab., March 1, 2004; 89(3): 1153 - 1159. [Abstract] [Full Text] [PDF]

				C. Flood, M. Gustafsson, R. E. Pitas, L. Arnaboldi, R. L. Walzem, and J. Boren Molecular Mechanism for Changes in Proteoglycan Binding on Compositional Changes of the Core and the Surface of Low-Density Lipoprotein-Containing Human Apolipoprotein B100 Arterioscler. Thromb. Vasc. Biol., March 1, 2004; 24(3): 564 - 570. [Abstract] [Full Text]

				R. Nijmeijer, M. Willemsen, C. J. L. M. Meijer, C. A. Visser, R. H. Verheijen, R. A. Gottlieb, C. E. Hack, and H. W. M. Niessen Type II secretory phospholipase A2 binds to ischemic flip-flopped cardiomyocytes and subsequently induces cell death Am J Physiol Heart Circ Physiol, November 1, 2003; 285(5): H2218 - H2224. [Abstract] [Full Text] [PDF]

				P. E. Szmitko, C.-H. Wang, R. D. Weisel, G. A. Jeffries, T. J. Anderson, and S. Verma Biomarkers of Vascular Disease Linking Inflammation to Endothelial Activation: Part II Circulation, October 28, 2003; 108(17): 2041 - 2048. [Full Text] [PDF]