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Cardiovascular Research 2000 47(1):159-165; doi:10.1016/S0008-6363(00)00060-2
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Copyright © 2000, European Society of Cardiology

Increase in plasma levels of secretory type II phospholipase A2 in patients with coronary spastic angina

Kiyotaka Kugiyama*, Yasutaka Ota, Hiroaki Kawano, Hirofumi Soejima, Hisao Ogawa, Seigo Sugiyama, Hideki Doi and Hirofumi Yasue

Department of Cardiovascular Medicine, Kumamoto University School of Medicine, Kumamoto, Japan

* Corresponding author. Tel.: +81-963-735-175; fax: +81-963-623-256 kiyo{at}gpo.kumamoto-u.ac.jp

Received 4 November 1999; accepted 28 February 2000


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Objective: Plasma levels of sPLA2 were increased in various chronic inflammatory diseases including coronary artery disease. Lipid products mediated through PLA2 have been shown to induce impairment of endothelium-dependent dilation, contraction of smooth muscle and proliferation of smooth muscle cells, all of which might lead to coronary spasm. Thus, this study investigated whether plasma levels of secretory non-pancreatic type II phospholipase A2 (sPLA2) may be increased in patients with coronary spastic angina, considering the possible link of sPLA2 with pathogenesis of coronary artery spasm. Methods: Plasma levels of sPLA2 in peripheral circulation, in coronary sinus and in aortic root were measured in 57 patients with coronary spastic angina, 46 patients with stable effort angina and 53 control patients by radioimmunoassay. Results: The peripheral plasma levels of sPLA2 were increased in patients with coronary spastic angina compared with control patients. In multivariate statistical analysis, the increase in sPLA2 levels was a significant risk for the presence of coronary spasm independent of other risk factors including C-reactive protein levels. The coronary sinus–arterial difference of plasma sPLA2 levels, reflecting sPLA2 released into the coronary circulation, was increased during coronary spasm induced by the intracoronary infusion of acetylcholine in patients with coronary spastic angina, but it remained unchanged both during the acetylcholine infusion and during myocardial ischemia provoked by rapid atrial pacing in patients with stable effort angina and in control patients. Conclusion: The increase in peripheral plasma levels of sPLA2 is a significant risk factor for the presence of coronary spasm and it may possibly reflect inflammatory activity in spasm coronary arteries.

KEYWORDS Acetylcholine; Atherosclerosis; Coronary disease; Infection/inflammation; Vasoconstriction/dilation


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
It has been shown that impairment of endothelium-dependent vasodilation as well as hypercontractile response of smooth muscle in coronary arteries may play an important role in the genesis of coronary spasm [1,2]. Although the precise mechanisms for coronary spasm remain unclear, atherosclerosis may underlie the functional alteration of these vascular cells in spasm coronary arteries [3]. In this context, a number of reports showed that atherosclerotic arteries have an impaired endothelium-dependent dilation and an increased constrictor response of smooth muscle [4,5] and that atheromatous plaques exist even in angiographically normal coronary arteries in patients with coronary spastic angina, assessed by intracoronary ultrasound techniques [6].

Local and systemic inflammatory responses are involved in atherogenesis [7–13]. Phospholipases A2 (PLA2) are ubiquitous enzymes that hydrolyze the sn-2-acyl bond of phospholipids of cell membranes and lipoproteins and yield free fatty acids and lysophospholipids, precursors of various proinflammatory lipid mediators including leukotrienes, eicosanoids, prostaglandins and platelets-activating factor (PAF) [14–16]. Previous studies showed that secretory non-pancreatic type II phospholipase A2 (sPLA2) importantly contributes to the pathogenesis of various inflammatory diseases [15,16]. Recently, sPLA2 was found to be highly expressed in human atherosclerotic arterial walls [17–19]. It was further demonstrated that transgenic mice expressing sPLA2 exhibited marked atherosclerotic lesions, suggesting that sPLA2 may have a primary role in the atherosclerotic development [20]. We have very recently shown that circulating plasma levels of sPLA2 are increased in patients with coronary artery disease (CAD) and that its levels predict clinical coronary events in patients with CAD [21]. Some lipid products mediated through PLA2 such as modified low-density lipoproteins (LDL), lysophosphatidylcholine, thromboxane A2, leukotrienes and PAF have been shown to induce impairment of endothelium-dependent dilation, contraction of smooth muscle and proliferation of smooth muscle cells [22–27], all of which might lead to coronary spasm. Thus, this study tested whether plasma levels of sPLA2 may be increased in patients with coronary spastic angina, considering the possible link of sPLA2 with pathogenesis of coronary artery spasm.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
2.1 Study patients
This study enrolled 81 consecutive patients with coronary spastic angina who underwent cardiac catheterization in Kumamoto University Hospital. The patients with coronary spastic angina fulfilled all of the following inclusion criteria: (1) spontaneous attacks of chest pain associated with ST segment elevation or depression on 12 leads electrocardiograms (ECG) or ambulatory ECG at rest. (2) coronary artery spasm (total or subtotal occlusion) in the left coronary arteries, demonstrated angiographically during the anginal attack of chest pain with ST segment changes resulting from the intracoronary infusion of acetylcholine (ACh), as reported previously [1,28]. (3) no previous myocardial infarction. Twenty-four patients were excluded because they had one of the following exclusion criteria; major surgery and trauma and serious infectious diseases within the previous 4 weeks, malignancies and chronic inflammatory diseases including rheumatoid arthritis, osteoarthritis and inflammatory bowel diseases. Finally, 57 (70%) of the 81 patients were included in this study. Patients characteristics are shown in Table 1.


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  		Table 1 Patients characteristicsa

 
This study also included 46 consecutive patients with stable effort angina and 53 consecutive control patients who underwent elective and diagnostic cardiac catheterization during the same study period as those with coronary spastic angina in this hospital. Both groups of patients were selected to match age and sex to those in patients with coronary spastic angina and did not have coronary spasm provoked by the intracoronary infusion of ACh. The included patients with stable effort angina had angiographic documentation of organic stenosis of >70% in the left coronary arteries, no previous myocardial infarction, and no episodes of angina at rest. The control patients underwent cardiac catheterization for atypical chest pain. Control patients had angiographically normal coronary arteries (<10% stenosis), normal left ventriculography, and no clinical evidence of coronary artery spasm and syndrome X. None of the study patients with stable effort angina and the control patients had any of the same exclusion criteria described above. All medications except sublingual nitroglycerin were withdrawn at least 3 days before the study in all study patients. None of the study patients took coumarin anticoagulant or antiplatelet agents before this study since this was their first time diagnosis. No study patient had taken nitroglycerin within 6 h before the study. Written informed consent was obtained from all patients before the study. This study was in agreement with the guidelines approved by the ethics committee at our institution. The investigation confirms with the principles outlined in the Declaration of Helsinki.

2.2 Blood sampling
Peripheral venous blood after an overnight fast was taken for assays of sPLA2 and C-reactive protein (CRP) levels just before cardiac catheterization in all study patients. Blood in the aortic root (AO) and coronary sinus (CS) was simultaneously taken for assays of sPLA2 and CRP levels at cardiac catheterization under the following conditions, (1) at baseline and during spasm associated with anginal pain and ischemic ST segment changes in the left coronary arteries provoked by the intracoronary infusion of ACh in all patients with coronary spastic angina, (2) at baseline and during the ACh infusion in 15 patients with stable effort angina and in all control patients, (3) at baseline and during anginal attack with ischemic ST segment depression provoked by rapid atrial pacing in 36 patients with stable effort angina.

2.3 Cardiac catheterization
A 6F Goodale-Lubin catheter (USCI) for blood sampling was positioned in the CS through the right antecubital vein [29]. After baseline blood sampling from the CS and AO, incremental doses of ACh (20, 50, and 100 µg/min for 1 min) were infused into the left coronary artery until coronary spasm was induced or the maximal dose was reached in all patients with coronary spastic angina, in all control patients and in 15 patients with stable effort angina, as previously reported [1,28]. A coronary angiogram was obtained at the end of each infusion. Subsequently, blood was again taken simultaneously from the CS and AO during coronary spasm in patients with coronary spastic angina and during the infusion of the maximum dose of ACh in patients with stable effort angina tested and in control patients. Coronary spasm was defined as total or subtotal occlusion of the epicardial coronary arteries associated with chest pain and ischemic ST segment changes [1,28]. In 36 patients with stable effort angina, rapid right atrial pacing was performed after the baseline blood sampling [29]. The pacing rate was increased to 130–140 beats per min and the blood from the CS and AO was taken when chest pain and ischemic ST segment changes appeared. Five patients with stable effort angina underwent both the ACh provocation study and the rapid atrial pacing study with a 15 min interval.

In control patients, the response of the luminal diameter at the proximal segment of left anterior descending coronary arteries to the infusion of ACh (50 µg/ml) was measured quantitatively using a computer-assisted coronary angiographic analysis system (Cardio 500, Kontron Instruments) [1]. The diameter response was expressed as a percent change from the baseline values on the angiograms taken just before the infusion.

2.4 Biochemical measurements
Blood samples, anticoagulated with EDTA, were immediately centrifuged at 3000 rpm at 4°C for 10 min. 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) [30,31]. This monoclonal antibody had no detectable cross-reactivity with human pancreatic PLA2 (type IB) [30,32]. The radioimmunoassay gave a linear response in a range from 78 to 5000 ng/dl of sPLA2 [30,32]. The inter-assay and intra-assay coefficients of variation were <8% [30,32]. The peripheral plasma levels of the immunoreactive sPLA2 showed a significant correlation with the calcium-dependent PLA2 activity in the citrated peripheral plasma, as previously reported [21,30]. Serum levels of CRP were measured using a N Latex CRP immunodetection kit (DADE BEHRING, Japan) [30,32]. This assay detects CRP levels in the range between 0.05 mg/dl and 20 mg/dl. Serum levels of total cholesterol, triglycerides and high-density lipoproteins (HDL)-cholesterol were measured by enzymatic methods [21] and the LDL-cholesterol levels were calculated as previously described [21].

2.5 Statistical analysis
Since sPLA2 levels were not distributed normally, the sPLA2 levels recorded are expressed as the median and range (25th and 75th percentiles) and nonparametric analyses were used. The Mann–Whitney U test was used to evaluate differences in sPLA2 levels between the two groups. The Wilcoxon signed rank test was used for comparison of paired levels of sPLA2. Spearman's rank correlation test was used for relations of sPLA2 levels with CRP levels and coronary diameter response to ACh. To evaluate higher sPLA2 levels as an independent risk factor for patients with coronary spastic angina, multiple logistic regression analysis was performed using patients with coronary spastic angina as a dependent variable and the following categorical covariates as independent variables; higher levels of sPLA2 (>346 ng/dl, arbitrarily defined as 75th percentile of the distribution of the sPLA2 levels in the study patients), age (≥70 y), sex (male), current smoking (defined as smoking at least 10 cigarettes per a day for ≥10 years), hypertension (>140/90 mmHg or requiring antihypertensive medication), diabetes mellitus (according to ADA report [33]), hypercholesterolemia (>220 mg/dl or the use of lipid-lowering medications), low HDL-cholesterol (<35 mg/dl), and higher CRP levels (>0.28 mg/dl, arbitrarily defined as the 75th percentile of the distribution of the CRP levels in the study patients). Multiple logistic regression analysis using the same categorical covariates was used for the evaluation of an independent association of higher levels of sPLA2 with the traditional risk factors. On scoring the number of coronary arteries with stenosis, stenosis of the left main coronary artery was counted as two vessel disease. One-way ANOVA was used for the comparison of mean values of continuous variables with normal distribution (expressed as mean±S.D.) among groups. Frequencies between two groups were compared by {chi}2 analysis. Statistical significance was defined as P<0.05. The analyses were performed partly using StatView 5.0 for the Macintosh.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
3.1 Comparison of clinical characteristics among the study groups
Of 57 patients with coronary spastic angina, 40 patients had normal coronary angiograms (less than 10% stenosis). The frequency of smoking in patients with coronary spastic angina was significantly higher than that in control patients and in patients with stable effort angina, as shown in Table 1. HDL-cholesterol levels in patients with coronary spastic angina were significantly lower compared with those in control patients (Table 1). The frequency of diabetes mellitus and hypertension in patients with stable effort angina was significantly higher than that in patients with coronary spastic angina and in control patients (Table 1). The number of the traditional coronary risk factors associated with individuals (age [≥70 y], histories of smoking, diabetes mellitus and hypertension, hypercholesterolemia and low HDL-cholesterol) was comparable between patients with coronary spastic angina and control patients, but it was greater in patients with stable effort angina than control patients (Table 1).

3.2 sPLA2 levels in the peripheral circulation
The distribution of the sPLA2 plasma levels in the peripheral circulation among the study patients was skewed and shifted to the lower levels. The sPLA2 levels were positively correlated with age and CRP levels ({rho}=0.33 and 0.37, respectively, P <0.0001 in both, n=156, respectively, by Spearman's rank correlation test). The levels were higher in patients with diabetes mellitus than those with non-diabetes (296 ng/dl [223,443] vs. 217 ng/dl [161,322], n=40 and 116, respectively, P=0.0006). In multiple logistic regression analysis, higher plasma levels of sPLA2 (>346 ng/dl) were significantly related with higher age (≥70 y) (Odds, 3.0; 95% CI, 1.1–8.3; P=0.03) and higher CRP levels (>0.28 mg/dl) (Odds, 7.1; 95% CI, 2.5–20.3; P=0.0003) among the traditional risk factors (age ≥70 y, male sex, smoking history, diabetes mellitus, hypertension, hypercholesterolemia, and low HDL-cholesterol) and the higher CRP levels.

The sPLA2 levels in patients with coronary spastic angina were significantly higher than those in control patients (242 ng/dl [172,387] vs. 185 ng/dl [156,241], n=57 and 53, respectively, P=0.008) and they were comparable with those in patients with stable effort angina (vs. 266 ng/dl [160,371], n=46, P=0.63). The sPLA2 levels in patients with stable effort angina were higher than those in control patients (P=0.003). In multiple logistic regression analysis, the higher sPLA2 levels were an independent risk factor for the presence of coronary spastic angina (Odds, 3.1; 95% CI, 1.1–9.2; P=0.03) among the covariates including age ≥70 y, male sex, smoking history, diabetes mellitus, hypertension, hypercholesterolemia, low HDL-cholesterol, the higher CRP levels (>0.28 mg/dl) and the higher sPLA2 levels (>346 ng/dl). The higher sPLA2 levels were not a significant risk factor for stable effort angina (Odds, 0.9; 95% CI, 0.33–3.0; P=0.99) among the same covariates in multivariate analysis.

The sPLA2 levels had a significant and negative correlation with the percent change of the coronary diameter from the baseline values to ACh infusion in control patients, as shown in Fig. 1.


Figure 1
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  		Fig. 1 Relation between sPLA2 and the % change in coronary diameter to the intracoronary infusion of acetylcholine (ACh, 50 µg/ml) in control patients.

 
3.3 sPLA2 levels in coronary circulation
The CS–AO differences of plasma sPLA2 levels, reflecting released sPLA2 into coronary circulation, were significantly increased during coronary spasm provoked by the ACh infusion compared with the baseline values in patients with coronary spastic angina, as shown in Fig. 2. However, there was no significant difference in CS–AO differences of plasma sPLA2 levels between before and during the ACh infusion in control patients and in patients with stable effort angina (Fig. 2). Also, there was no difference in them between before and during anginal attack provoked by rapid atrial pacing in patients with stable effort angina (Fig. 2). The aortic sPLA2 levels were not significantly changed between the baseline and during coronary spasm in patients with coronary spastic angina, at baseline and during the ACh infusion in patients with stable effort angina and in control patients, and before and during anginal attack induced by the rapid atrial pacing in patients with stable effort angina (Table 2). The levels in CS were significantly increased during coronary spasm compared with the baseline values in patients with coronary spastic angina, but remained unchanged between before and after the ACh infusion in patients with stable effort angina and in control patients, and before and during anginal attack in patients with stable effort angina (Table 2). Either the AO or CS levels of sPLA2 were higher in patients with coronary spastic angina and in patients with stable effort angina than the respective levels in control patients (Table 2). CRP levels were comparable between CS and AO at baseline (0.23 mg/dl [0.06, 0.25] vs. 0.24 mg/dl [0.05, 0.27], respectively, n=57, P=n.s.) and during coronary spasm (0.24 mg/dl [0.05, 0.27] vs. 0.25 mg/dl [0.07, 0.29], respectively, n=57, P=n.s.) in patients with coronary spastic angina.


Figure 2
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  		Fig. 2 Comparison of coronary sinus–arterial difference of plasma sPLA2 levels between before and during ACh provocation test in control patients (n=53), in patients with coronary spastic angina (n=57), and in those with stable effort angina (n=15) and before and during rapid atrial pacing in patients with stable effort angina (n=36). Horizontal center bars represent median values, upper and lower bars represent 75th and 25th percentiles, respectively. Wilcoxon signed rank test was used for comparison of the paired levels.

 

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  		Table 2 sPLA2 levels in aortic root (AO) and coronary sinus (CS) before and during ACh provocation test or rapid atrial pacinga

 

   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
The present study demonstrated that plasma levels of sPLA2 were increased in patients with coronary spastic angina compared with control patients and that the increase in sPLA2 levels was an independent risk for the presence of coronary spasm. Some of the lipid products through PLA2 such as modified LDL, lysophosphatidylcholine, leukotrienes, thromboxane A2 and PAF are potent vasoconstrictors and could induce proliferation of smooth muscle cells [22–27]. In this context, the present study further showed that plasma levels of sPLA2 were positively correlated with extent of coronary constrictor response to ACh. Thus, these findings suggest that the sPLA2 levels may be intimately linked with the pathogenesis of coronary spasm. The present study showed that sPLA2 was released into the coronary circulation during coronary spasm induced by the intracoronary infusion of ACh in patients with coronary spastic angina. The release of sPLA2 into the coronary circulation was unlikely to be due to myocardial ischemia because sPLA2 levels were not significantly increased in the coronary circulation during myocardial ischemia induced by the rapid atrial pacing in patients with stable effort angina. In addition, ACh alone did not seem to cause the increase in sPLA2 levels in the coronary circulation in patients with coronary spastic angina since sPLA2 levels were not increased by the ACh infusion in both control patients and patients with stable effort angina. The released sPLA2 into the coronary circulation by repetitive occurrence of coronary spasm might partly have contributed to its increase in the peripheral circulation in patients with coronary spastic angina.

The sources of sPLA2 released into the coronary circulation remain to be determined. It has been shown that sPLA2 is expressed in smooth muscle cells, macrophages and endothelial cells and abundantly exists in extracellular matrix in atherosclerotic arterial walls [15–19]. It is thus possible that coronary spasm may trigger the release of sPLA2 present in coronary arterial walls into coronary circulation in patients with coronary spastic angina. We have previously shown that platelets in the coronary circulation were activated during coronary spasm in patients with coronary spastic angina [34]. Platelets contain sPLA2 and secrete it during the activation [35]. Thus, platelets-derived sPLA2 may be another possible source of its increase in coronary circulation during coronary spasm in patients with coronary spastic angina.

Local and systemic inflammatory stimuli might induce synthesis of sPLA2 in atheromatous plaques of systemic arteries and release it into the circulation, resulting in the elevation of the sPLA2 plasma levels in patients with CAD in proportion to number of coronary risk factors present [7–13,21]. Plasma levels of CRP, a hepatically-derived and systemic inflammatory marker, are increased in patients with unstable angina [7,8]. sPLA2 is an inflammatory marker and its peripheral plasma levels were also increased in proportion to the extent of systemic inflammation in various diseases [15,16,30,32]. This was supported by the present finding that there was a positive correlation between plasma levels of CRP and sPLA2. However, plasma levels of sPLA2 but not CRP were increased in patients with coronary spastic angina, suggesting that the increase in peripheral plasma levels of sPLA2 in patients with coronary spastic angina may be independent of the mechanism, i.e. systemic inflammation, which leads to the increase in CRP levels. In addition, the number of risk factors associated with patients with coronary spastic angina was comparable with that of control patients, suggesting that highly extensive systemic atherosclerosis was unlikely to develop in patients with coronary spastic angina. Previous histological studies have shown that inflammatory cells were clustered in spasm coronary arteries [36,37]. Furthermore, a recent study [38] reported that local treatment of coronary arteries with interleukin-1β, an inflammatory cytokine, induced coronary spasm in animal models. Taken together, it is possible that the increase in plasma levels of sPLA2 in either the coronary or peripheral circulation may reflect inflammatory activity locally in spasm coronary arteries in patients with coronary spastic angina. In patients with stable effort angina, the number of risk factors present was increased compared with control patients. CRP levels tended to be increased in these patients, although the increase did not reach a significant level. Thus, the increase in peripheral plasma of sPLA2 in patients with stable effort angina may possibly be derived from systemic atherosclerotic arteries or other organs.

It should be noted that HDL-cholesterol levels were significantly low in patients with coronary spastic angina, a finding which is consistent with a previous report [39]. HDL contain PAF-acetylhydrolase and paraoxonase that can detoxify PAF and other toxic phospholipids [40]. In addition, we previously reported that apoA-1 and HDL can absorb lysophosphatidylcholine and other hydrophilic phospholipids [41]. Thus, low HDL levels might augment vasoconstrictive effects of some lipids produced through sPLA2.

The present study is limited because of lack of information regarding the relation between the release of sPLA2 levels into the coronary circulation and the actual extent of coronary atherosclerosis, assessed by the intravascular ultrasound techniques.

In conclusion, sPLA2 may be intimately linked with pathogenesis of coronary artery spasm. The increase in plasma sPLA2 levels may possibly reflect inflammatory activity in spasm coronary arteries.

Time for primary review 21 days.


   Acknowledgements
 
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.


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 

  1. Kugiyama K., Yasue H., Okumura K., et al. Nitric oxide activity is deficient in spasm arteries of patients with coronary spastic angina. Circulation (1996) 94:266–271.[Abstract/Free Full Text]
  2. Kugiyama K., Murohara T., Yasue H., et al. Increased constrictor response to acetylcholine of the isolated coronary arteries from patients with variant angina. Int J Cardiol (1995) 52:223–233.[CrossRef][Web of Science][Medline]
  3. Suzuki H., Kawai S., Aizawa T., et al. Histological evaluation of coronary plaque in patients with variant angina: relationship between vasospasm and neointimal hyperplasia in primary coronary lesions. J Am Coll Cardiol (1999) 33:198–205.[Abstract/Free Full Text]
  4. McLenachan J.M., Williams J.K., Fish R.D., Ganz P., Selwyn A.P. Loss of flow-mediated endothelium-dependent dilation occurs early in the development of atherosclerosis. Circulation (1991) 84:1273–1278.[Abstract/Free Full Text]
  5. Tanner F.C., Boulanger C.M., Lüscher T.F. Endothelium-derived nitric oxide, endothelin, and platelet vessel wall interaction: alterations in hypercholesterolemia and atherosclerosis. Semin Thromb Hemost (1993) 19:167–175.[Web of Science][Medline]
  6. Yamagishi M., Miyatake K., Tamai J., Nakatani S., Koyama J., Nissen S.E. Intravascular ultrasound detection of atherosclerosis at the site of focal vasospasm in angiographically normal or minimally narrowed coronary segments. J Am Coll Cardiol (1994) 23:352–357.[Abstract]
  7. Liuzzo G., Biasucci L.M., Gallimore J.R., et al. The prognostic value of C-reactive protein and serum amyloid a protein in severe unstable angina. New Engl J Med (1994) 331:417–424.[Abstract/Free Full Text]
  8. Berk B.C., Weintraub W.S., Alexander R.W. Elevation of CRP in ‘active’ CAD. Am J Cardiol (1990) 65:168–172.[CrossRef][Web of Science][Medline]
  9. Ridker P.M., Rifai N., Pfeffer M.A., et al. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators. Circulation (1998) 98:839–844.[Abstract/Free Full Text]
  10. Libby P. Molecular bases of the acute coronary syndromes. Circulation (1995) 91:2844–2850.[Free Full Text]
  11. Falk E., Shah P.K., Fuster V. Coronary plaque disruption. Circulation (1995) 92:657–671.[Free Full Text]
  12. Ross R. Atherosclerosis – an inflammatory disease. New Engl J Med (1999) 340:115–126.[Free Full Text]
  13. Hansson G.K., Jonasson L., Seifert P.S., Stemme S. Immune mechanisms in atherosclerosis. Arteriosclerosis (1989) 9:567–578.[Abstract/Free Full Text]
  14. Dennis E.A. Diversity of group types, regulation, and function of phospholipase A2. J Biol Chem (1994) 269:13057–13060.[Free Full Text]
  15. Pruzanski W., Vadas P. Phospholipase A2-a mediator between proximal and distal effectors of inflammation. Immunol Today (1991) 12:143–146.[Web of Science][Medline]
  16. Murakami M., Kudo I., Inoue K. Secretory phospholipase A2. J Lipid Mediat Cell Signalling (1995) 12:119–130.[CrossRef][Web of Science][Medline]
  17. Menschikowski M., Kasper M., Lattke P., et al. Secretory group II phospholipase A2 in human atherosclerotic plaques. Atherosclerosis (1995) 118:173–181.[CrossRef][Web of Science][Medline]
  18. Hurt-Camejo E., Andersen S., Standal R., et al. 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]
  19. Elinder L.S., Dumitrescu A., Larsson P., Hedin U., Frostegård J., Claesson H.E. Expression of phospholipase A2 isoforms in human normal and atherosclerotic arterial wall. Arterioscler Thromb Vasc Biol (1997) 17:2257–2263.[Abstract/Free Full Text]
  20. Ivandic B., Castellani L.W., Wang X.P., et al. Role of group II secretory phospholipase A2 in atherosclerosis: 1. Increased atherogenesis and altered lipoproteins in transgenic mice expressing group IIa phospholipase A2. Arterioscler Thromb Vasc Biol (1999) 19:1284–1290.[Abstract/Free Full Text]
  21. Kugiyama K., Ota Y., Takazoe K., et al. Circulating levels of secretory type II phospholipase A2 predict coronary events in patients with coronary artery disease. Circulation (1999) 100:1280–1284.[Abstract/Free Full Text]
  22. Kugiyama K., Kerns S.A., Morrisett J.D., Roberts R., Henry P.D. Impairment of endothelium-dependent arterial relaxation by lysolecithin in modified low-density lipoproteins. Nature (1990) 344:160–162.[CrossRef][Medline]
  23. Murohara T., Kugiyama K., Ohgushi M., Sugiyama S., Ohta Y., Yasue H. LPC in oxidized LDL elicits vasocontraction and inhibits endothelium-dependent relaxation. Am J Physiol (1994) 267:H2441–H2449.[Web of Science][Medline]
  24. Ohmori M., Kuzuya T., Kodama K., Nanto S., Kamada T., Tada M. Thromboxane A2 as an enhancing factor of coronary vasospasticity in variant angina. Jpn Circ J (1987) 51:495–502.[Medline]
  25. Pakala R., Willerson J.T., Benedict C.R. Effect of serotonin, thromboxane A2, and specific receptor antagonists on vascular smooth muscle cell proliferation. Circulation (1997) 96:2280–2286.[Abstract/Free Full Text]
  26. Allen S.P., Chester A.H., Dashwood M.R., Tadjkarimi S., Piper P.J., Yacoub M.H. Preferential vasoconstriction to cysteinyl leukotrienes in the human saphenous vein compared with the internal mammary artery. Implications for graft performance. Circulation (1994) 90:515–524.[Abstract/Free Full Text]
  27. Soloviev A.I., Braquet P. Platelet-activating factor (PAF) induces contraction of saponin-skinned smooth muscle of coronary artery. Lipids (1991) 26:1274–1276.[CrossRef][Web of Science][Medline]
  28. Yasue H., Horio Y., Nakamura N., et al. Induction of coronary artery spasm by acetylcholine in patients with variant angina: possible role of the parasympathetic nervous system in the pathogenesis of coronary artery spasm. Circulation (1986) 74:955–963.[Abstract/Free Full Text]
  29. Nishiyama K., Ogawa H., Yasue H., et al. Heparin-releasable endothelial cell-associated tissue factor pathway inhibitor (TFPI) is increased in the coronary circulation after coronary spasm in patients with coronary spastic angina. Thromb Res (1998) 89:137–146.[CrossRef][Web of Science][Medline]
  30. Matsuda Y., Ogawa M., Sakamoto K., et al. Development of a radioimmunoassay for human group-II phospholipase A2 and demonstration of postoperative elevation. Enzyme (1991) 45:200–208.[Web of Science][Medline]
  31. 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.[CrossRef][Web of Science][Medline]
  32. 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]
  33. The expert committee on the diagnosis and classification of diabetes mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care (1997) 20:1183–1197.[Web of Science][Medline]
  34. Ogawa H., Yasue H., Okumura K., et al. Platelet-derived growth factor is released into the coronary circulation after coronary spasm. Coronary Artery Dis (1993) 4:437–442.[Web of Science][Medline]
  35. Kramer R.M., Hession C., Johansen B., et al. Structure and properties of a human non-pancreatic phospholipase A2. J Biol Chem (1989) 264:5768–5775.[Abstract/Free Full Text]
  36. Kohchi K., Takebayashi S., Hiroki T., Nobuyoshi M. Significance of adventitial inflammation of the coronary artery in patients with unstable angina: results at autopsy. Circulation (1985) 71:709–716.[Abstract/Free Full Text]
  37. Forman M.B., Oates J.A., Robertson D., Robertson R.M., Roberts L.J. II, Virmani R. Increased adventitial mast cells in a patient with coronary spasm. New Engl J Med (1985) 313:1138–1141.[Web of Science][Medline]
  38. Shimokawa H., Ito A., Fukumoto Y., et al. Chronic treatment with interleukin-1 β induces coronary intimal lesions and vasospastic responses in pigs in vivo. The role of platelet-derived growth factor. J Clin Invest (1996) 97:769–776.[Web of Science][Medline]
  39. Kuhn F.E., Mohler E.R., Satler L.F., Reagan K., Lu D.Y., Rackley C.E. Effects of high-density lipoprotein on acetylcholine-induced coronary vasoreactivity. Am J Cardiol (1991) 68:1425–1430.[CrossRef][Web of Science][Medline]
  40. Watson A.D., Navab M., Hama S.Y., et al. Effect of platelet activating factor-acetylhydrolase on the formation and action of minimally oxidized low density lipoprotein. J Clin Invest (1995) 95:774–782.[Web of Science][Medline]
  41. Ota Y., Kugiyama K., Sugiyama S., Matsumura T., Terano T., Yasue H. Complexes of apoA-1 with phosphatidylcholine suppress dysregulation of arterial tone by oxidized LDL. Am J Physiol (1997) 273:H1215–H1222.[Web of Science][Medline]

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E. Hurt-Camejo, G. Camejo, H. Peilot, K. Oorni, and P. Kovanen
Phospholipase A2 in Vascular Disease
Circ. Res., August 17, 2001; 89(4): 298 - 304.
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