lipocalin-type prostaglandin d synthase is associated with

Circulation Journal Vol.75, April 2011

Circulation JournalOfficial Journal of the Japanese Circulation Societyhttp://www.j-circ.or.jp

rostaglandin (PG) D2, a metabolite of PGH2, has vari-ous physiological actions, including the regulation of sleep1 and nociception,2 inhibition of platelet aggre-

gation,3 and induction of vasodilatation.4 Lipocalin-type PGD synthase (L-PGDS) is one of the enzymes involved in the biosynthesis of PGD2, as it catalyzes the isomerization of PGH2 to PGD2.5 L-PGDS is localized in the central nervous system and male genital organs of various mammals, and is secreted as β-trace into the closed compartment of these tissues separated from the systemic circulation.6,7 We previ-ously reported that L-PGDS is present in the human heart, and secreted into the coronary circulation.8 An enzyme-linked immunosorbent assay (ELISA) for L-PGDS has been estab-lished to determine its serum level,9 which has been shown to be increased in patients with stable angina pectoris, essen-tial hypertension, and renal dysfunction.10–12

Editorial p 784

Coronary spasm plays an important role in the pathogene-sis of ischemic heart disease; however, the conclusive mech-anism of coronary vasospasm is still unknown.13–15 Currently, there are no excellent biomarkers that indicate the presence of vasospastic angina (VSA). Acetylcholine (ACh) has been used as a pharmacological tool to induce coronary vasospasm and to evaluate endothelial function,16 because endothelial dysfunction has been implicated as a crucial factor in the pathogenesis of coronary vasospasm in patients with VSA.13 Early reports showed a strong correlation between PGD2- and ACh-induced relaxation in isolated segments of bovine coronary arteries with intact endothelium.4 It also has been shown that shear stress promotes PGD2 production by stimu-

Received September 7, 2010; revised manuscript received November 16, 2010; accepted December 1, 2010; released online February 11, 2011 Time for primary review: 13 days

Department of Cardiovascular and Respiratory Medicine (T.M., T.O., H.H., I.N., M.H.), Intensive Care Unit (Y.E., T.Y.), Shiga University of Medical Science, Otsu; Central Research Institute, Maruha Nichiro Holdings, Inc, Tsukuba (H.O.); Department of Cardiology, Okamura Memorial Hospital, Shizuoka (Y.T.); and Department of Behavioral Biology, Osaka Bioscience Institute, Suita (Y.U.), Japan

Mailing address: Tetsuya Matsumoto, MD, Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Seta Tsukinowa, Otsu 520-2192, Japan. E-mail: [email protected]

ISSN-1346-9843 doi: 10.1253/circj.CJ-10-0902All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected]

Lipocalin-Type Prostaglandin D Synthase Is Associated With Coronary Vasospasm and Vasomotor Reactivity

in Response to AcetylcholineTetsuya Matsumoto, MD; Yutaka Eguchi, MD; Hiroshi Oda, PhD; Tetsunobu Yamane, MD;

Yasuhiro Tarutani, MD; Tomoya Ozawa, MD; Hideki Hayashi, MD; Ichiro Nakae, MD; Minoru Horie, MD; Yoshihiro Urade, PhD

Background: Lipocalin-type prostaglandin D synthase (L-PGDS) catalyzes the biosynthesis of PGD2, which acts as an anticoagulant, vasodilator, and inflammatory mediator. We examined the serum L-PGDS level, coronary macro- and microvasomotor functions, and their relationship in patients with chest pain and angiographically nor-mal coronary arteries.

Methods and Results: The study included 96 patients who underwent diagnostic coronary angiography and had angiographically normal coronary arteries. Blood flow of the left anterior descending coronary artery (LAD) was analyzed by Doppler guidewire examination. Serum L-PGDS level was determined by ELISA. Infusion of acetylcholine (ACh) induced vasospasm of the LAD in all patients with vasospastic angina (VSA) (n=45), but in none of the patients without VSA (n=51). There were no significant differences in the baseline clinical characteris-tics of the nonVSA and VSA groups, except for the frequency of smoking. Serum L-PGDS level in the VSA group was significantly higher than that in the nonVSA group (77.1±4.4 vs. 63.9±2.5 μg/dl, P<0.01). Significant negative correlations were observed between the degree of LAD vasomotion in response to ACh and serum L-PGDS level (3 μg/min: r=–0.33; 10 μg/min: r=–0.35; 30 μg/min: r=–0.33, P<0.01).

Conclusions: The L-PGDS level was elevated in patients with VSA and was associated with epicardial coro-nary vasomotion in response to ACh. (Circ J 2011; 75: 897 – 904)

Key Words: Acetylcholine; Coronary spasm; Lipocalin-type prostaglandin D synthase

P

ORIGINAL ARTICLEIschemic Heart Disease


898 MATSUMOTO T et al.

lating L-PGDS expression in vascular endothelial cells in response to blood flow.17 Vasoconstriction can reduce blood flow and increase arterial shear stress.18 Nevertheless, the relationship between coronary vasomotor function and the serum L-PGDS level has not been assessed in patients with angiographically normal coronary arteries. Thus, in the pres-ent study we examined the serum L-PGDS level, coronary macro- and microvasomotor functions, and their relationship in patients with chest pain and angiographically normal coro-nary arteries.

MethodsStudy PatientsThe study population consisted of patients with chest pain who underwent diagnostic cardiac catheterization and were shown to have angiographically normal coronary arteries. The study protocol was approved by the institutional Ethical Committee on Human Research, and written informed con-sent was given by all the patients. Patients with myocardial infarction, significant organic stenosis of the coronary arteries, congestive heart failure, congenital heart disease, cardiomy-opathy, severe valvular heart disease, non-sinus rhythm, or apparent inflammatory disease were excluded from the study. Patients who had clinically apparent atherosclerotic cere-brovascular disease, peripheral artery disease, or renal dys-function (creatinine ≥1.2 mg/dl) were also excluded. Calcium blockers and nitrates were discontinued for at least 72 h before the study. Blood pressure was measured in the morn-ing of the day of coronary angiography.

ProtocolRight and left cardiac catheterization was performed between 9 and 11 am while the patients were in the fasting state. After a diagnostic coronary angiographic study, incremental doses of ACh were injected into the right coronary artery (20 and 50 μg), as described previously.15 Patients in whom this did not elicit right coronary spasm were enrolled in the study. A

5F Judkins catheter was introduced into the left main coro-nary artery by the radial approach, and a 0.014-inch Doppler-tipped guidewire (FloWire, Volcano Therapeutics Inc) was advanced through the Judkins catheter.19 The wire tip was positioned in a proximal segment of the left anterior descend-ing coronary artery (LAD) that was free of any major branches within 1 cm from the tip, thus permitting adequate measure-ment of blood flow velocity. All drugs were infused directly into the left main coronary artery via a 3F coronary-infusion catheter (Cordis Endovascular Systems Inc) at infusion rates between 0.5 and 1 ml/min.

Baseline coronary angiography and measurement of coro-nary blood flow (CBF) velocity were performed. ACh-induced vasomotion was estimated from the dose – response curve obtained with incremental 2-min intracoronary infusions of ACh. ACh was started at 3 μg/min, and then increased to 10 and 30 μg/min. Thus, all the control subjects and the VSA patients received doses up to 100 μg/min, except for 7 patients in whom ACh at a concentration of 30 μg/min caused coro-nary vasospasm. Coronary angiography and measurement of CBF velocity were performed after each infusion. Subse-quently, nitroglycerin was given at 250 μg into the left coro-nary artery over 20 s, which relieved the coronary vasospasm. Finally, intracoronary administration of 12 mg papaverine for 20 s after an additional 10 min, by which time the CBF veloc-ity and aortic pressure had returned to their baseline levels. Maximal CBF velocity was measured after the infusion of papaverine. Coronary angiography was performed at 2 min after the infusion of nitroglycerin or papaverine. During the study, phasic and mean aortic blood pressure, heart rate, and 12-lead ECG were continuously monitored using a poly-graph system (Nihon-Kohden Kogyo Co).

Quantitative Coronary Angiography and Measurement of CBFCoronary cineangiograms were recorded using a Philips cineangiographic system (Philips Medical Systems). The change in diameter of the LAD was measured in a vessel segment 2.5 mm beyond the tip of the Doppler guidewire.

Figure 1. Changes in coronary artery diameter and coronary blood flow of the left anterior descending artery induced by incre-mental intracoronary infusions of acetylcholine in the vasospastic angina (VSA) group (blue circle) and the nonVSA group (red circle). *P<0.001 vs. nonVSA group. **P<0.0001 vs. nonVSA group. Values are mean ± SEM.


899Prostaglandin D2 and Coronary Vasospasm

Coronary angiograms were taken in the right caudal anterior oblique or right cranial anterior oblique position with adequate angulation to allow clear visualization of the left coronary artery. Coronary angiograms were analyzed by quantitative coronary angiography using a Cardiovascular Measurement System (QCA-CMS, MEDIS Medical Imaging Systems). Measurements were made 3 times, and the averaged value was used for analysis. Peak CBF velocity was continuously monitored using a fast Fourier transform-based spectral ana-lyzer (FloMap, Cardiometrics Inc). CBF was calculated as π× average peak CBF velocity × 0.125 × (arterial diameter)2. Vessel diameter and CBF velocity were analyzed by investi-gators who were unaware of the sequence of interventions.

Measurement of Serum L-PGDS LevelFasting peripheral blood was collected through an arterial

Table 1. Baseline Characteristics of the Study Group

NonVSA (n=51) VSA (n=45) P value

Age, years 61±2 61±2 NS

Gender, M/F 31/20 30/15 NS

Smoking 14 (28%) 27 (60%) <0.01

Body mass index, kg/m2 24.2±0.4 23.5±0.4 NS

Systolic AP, mmHg 137.6±2.2 143.8±4.0　　 NS

Diastolic AP, mmHg 70.5±1.4 73.4±1.8 NS

Heart rate, beats/min 69.4±5.2 68.0±2.6 NS

Total cholesterol, mg/dl 188.6±4.4 189.1±5.2　　 NS

HDL cholesterol, mg/dl 52.0±3.7 45.1±2.2 NS

LDL cholesterol, mg/dl 114.3±4.6 116.4±4.6　　 NS

Triglyceride, mg/dl 119.8±6.8 139.0±10.0 NS

Diabetes mellitus, n 12 (24%) 5 (11%) NS

L-PGDS, mg/dl 63.9±2.5 77.1±4.4 <0.01

Data are mean ± SEM.VSA, vasospastic angina; AP, arterial pressure; HDL, high-density lipoprotein; LDL, low-density lipoprotein; L-PGDS, lipocalin-type prostaglandin D synthase.

Table 2. Correlations Between Plasma L-PGDS Level and Other Parameters

r P value

Age (years) 0.089 0.3896

Sex (male =1) 0.3159

VSA (yes =1) 0.0088

Smoking (yes =1) 0.0342

Diabetes mellitus (yes =1) 0.6599

Hypertension (yes =1) 0.6599

Total cholesterol (mg/dl) 0.121 0.2390

Triglycerides (mg/dl) 0.076 0.4640

HDL cholesterol (mg/dl) 0.073 0.5180

LDL cholesterol (mg/dl) 0.150 0.1585

Abbreviations see in Table 1.

Figure 2. Serum level of L-PGDS in smokers and nonsmokers in the vasospastic angina (VSA) group and nonVSA group. Values are mean ± SEM. L-PGDS, lipocalin-type prostaglandin D synthase.



sheath just prior to angiography. The blood sample was im-mediately centrifuged at 1,500 g for 15 min at room tempera-ture. The serum was frozen and stored at –80°C until analysis. L-PGDS level was determined by sandwich ELISA with monoclonal antibodies (MAb) 1B7 and 7F5 as described previously.9,20 In brief, the samples were incubated at 25°C for 90 min in Maxi Sorp F96 microtiter plates (Nalge Nunc, Roskilde, Denmark) precoated with unlabelled MAb-7F5 (10 mg/L) at 4°C overnight. After a wash, the plates were incubated at 25°C with peroxidase-conjugated MAb-1B7 (2.0 μg/ml) for 90 min. Thereafter, substrate containing 3,3’, 5,5’-tetramethylbenzidine (BM-blue-POD substrate; Roche Diagnostics) was added to each well, and the reaction was stopped by adding 1 mol/L sulfuric acid. The plates were read

on a Spectra-Max 250 microplate reader (Molecular Devices, Sunnyvale, CA, USA) at 450 nm. All samples were measured in duplicate and the results were averaged.

Statistical AnalysisData are expressed as mean ± SE. Discrete variables are ex-pressed as counts or percentages and compared using chi-squared test. Continuous variables were compared using the un-paired Student’s t-test or 1-way analysis of variance (ANOVA). When serial changes in coronary vasomotor responses in response to graded doses of ACh were compared, we used 2-way ANOVA for repeated measures between groups. Uni-variate analysis of the association between L-PGDS and other parameters was performed using linear regression. For the

Figure 3. Relationship between serum L-PGDS level and changes in coronary diameter induced by acetylcholine (ACh) at doses of 3, 10 and 30 μg/min in the vasospastic angina (VSA) group (blue circle) and nonVSA group (red circle). L-PGDS, lipocalin-type prostaglandin D synthase.



regression analysis, sex, hypertension, diabetes, and smoking were assessed as categorical variables. Male sex, the pres-ence of VSA, hypertension, diabetes and smoking habit were coded as ‘1’, and female sex, the absence of VSA, hyperten-sion, diabetes or smoking habit as ‘0’. The other parameters were assessed as continuous variables. A 2-tailed P value <0.05 was considered to be statistically significant.

ResultsProvocation of Coronary Vasospasm and Coronary Vasomotor ResponsesInfusion of ACh induced coronary vasospasm of the LAD in association with chest pain or ischemic ECG changes in all

patients in the VSA group (n=45), but in none of the non-VSA group (n=51). The percent change in the diameter of the LAD induced by ACh at a dose of 100 μg was –21±3% in the nonVSA group. In the nonVSA group, intracoronary infusion of ACh did not induce coronary vasospasm, chest pain, or ischemic ECG changes. In the VSA group, coronary vasospasm of the LAD was induced by ACh infusion at 30 μg/min in 7 patients and at 100 μg/min in the remaining 38 patients. In 15 patients in the VSA group, coronary vaso-spasm of the LAD was accompanied by spasm of the left cir-cumflex coronary artery; 5 of those 15 patients showed focal spasm of the left circumflex coronary artery prior to the LAD spasm induced by ACh infusion at 30 μg/min, but received doses up to 100 μg/min.

Figure 4. Relationship between serum L-PGDS level and change in coronary blood flow induced by acetylcholine (ACh) at doses of 3, 10 and 30 μg/min in the vasospastic angina (VSA) group (blue circle) and nonVSA group (red circle). L-PGDS, lipocalin-type prosta-glandin D synthase.



ACh, given at doses of 3, 10 and 30 μg/min, caused mar-ginal vasoconstriction in the nonVSA group, but produced dose-dependent constriction of the LAD artery in the VSA group (Figure 1 Left). The increases in CBF induced by the 3 doses of ACh in the VSA group were significantly smaller than those in the nonVSA group (Figure 1 Right).

The change in dilatation of the LAD in response to nitro-glycerin at 250 μg in the VSA group was significantly higher than that in the nonVSA group (23.4±2.3% vs. 17.7±1.6%, P<0.05). The increase in CBF in response to papaverine at 12 mg did not differ between the nonVSA and VSA groups (381±20% vs. 344±28%).

L-PGDS and Clinical CharacteristicsThe clinical characteristics of the 2 groups are shown in Table 1. There were no significant differences in the line clinical characteristics of the nonVSA and VSA groups, except for the frequency of smoking. The 2 groups did not differ in age, sex, body mass index, arterial pressure, lipid parameters, or frequency of diabetes.

The average serum L-PGDS level in the VSA group was significantly higher than that in the nonVSA group (77.1±4.4 vs. 63.9±2.5 μg/dl, P<0.01) (Table 1). It was associated with smoking status, but not with age, sex, lipid parameters, or the presence of diabetes or hypertension (Table 2). Among all smokers, the serum level of L-PGDS in VSA patients was higher than that in nonVSA patients (Figure 2). The serum level of L-PGDS did not differ between smokers and non-smokers in either the nonVSA or VSA group (Figure 2).

L-PGDS and Coronary Vasomotor ResponsesSignificant negative correlations were observed between the degree of LAD vasomotion in response to ACh and the serum L-PGDS level (3 μg/min: r=–0.33; 10 μg/min: r=–0.35; 30 μg/min: r=–0.33, P<0.01) (Figure 3). No significant cor-relation was observed between the CBF response to ACh (3, 10 and 30 μg/min) and serum L-PGDS level (Figure 4).

Serum L-PGDS level did not correlate with coronary vaso-dilation induced by nitroglycerin or with the increase in CBF induced by papaverine (Figure 5).

DiscussionThis results of this study demonstrated that the serum level of L-PGDS was elevated in patients with VSA, and that the level was associated with the degree of coronary vasocon-striction in response to ACh.

L-PGDS is 1 of the enzymes that catalyze PGD2 synthe-sis.7 It is also a member of the lipocalin family, a group of secretory proteins transporting small hydrophobic molecules, including retinoids. Therefore, L-PGDS has 2 functions, as a PGD2-producing enzyme within cells and as a lipophilic ligand-binding protein after secretion into the extracellular space. Much effort has been made for a long time to elucidate the role of PGD2 in the brain, and it has been proved that PGD2 generated in the central nervous system is involved in the modulation of neural functions such as sleep induction1 and nociception.2 Although the role of PGD2 in atherogene-sis is not well understood, we previously reported that PGD2 participates in the pathogenesis of coronary atherosclerosis.8 It has been shown that L-PGDS localizes in human cardio-vascular tissue, including smooth muscle cells, endothelium, and coronary atheromatous plaques, and is secreted into the coronary circulation.8 PGD2 can inhibit platelet aggregation3 and induce endothelium-dependent coronary vasodilatation.4

In the present study, total cholesterol, low-density lipo-protein, high-density lipoprotein, triglycerides, diabetes, and body mass index were not associated with coronary vaso-spasm, consistent with previous reports.14,15 L-PGDS level was associated with smoking status, but not with age, sex, lipid parameters, or the presence of diabetes or hypertension. Among all smokers, the serum level of L-PGDS in VSA patients was higher than that in nonVSA patients, although the serum level of L-PGDS did not differ between smokers

Figure 5. Relationship between serum L-PGDS level and coronary vasomotor response induced by 0.25 mg nitroglycerin and 12 mg papaverine in the vasospastic angina (VSA) group (blue circle) and nonVSA group (red circle). L-PGDS, lipocalin-type prostaglandin D synthase.



and non-smokers in either the nonVSA or VSA group. Smok-ing is a major risk factor for VSA without significant coronary atherosclerosis.15 Chronic low-grade inflammation, which is in part induced by smoking, is a contributing factor in the genesis of VSA.21 Cyclooxygenase-mediated prostanoids are important mediators of the inflammatory and anti-inflamma-tory processes. Thus, L-PGDS and cigarette smoking may join in the pathogenesis of coronary spasm through inflam-matory processes, oxidative stress and endothelial dysfunc-tion. It has been shown that the L-PGDS level is increased in patients with stable angina pectoris, essential hypertension, and renal dysfunction,10–12 so we excluded patients with serum creatinine ≥1.2 mg/dl from our study. The L-PGDS level may be associated with coronary spasm as well as with athero-sclerosis. It has been shown that laminar fluid shear stress increases the expression of L-PGDS mRNA in vascular endo-thelial cells.17 In heme oxygenase-2-deficient mice, L-PGDS expression may be induced in the myocardium to cope with the hemodynamic stress generated by chronic hypoxemia.22 It is possible that the delivery of L-PGDS could provide new therapeutic modalities to prevent and treat coronary vaso-spasm.

An abnormal coronary vasomotor response to ACh is a de-monstrable constrictor response resulting from direct smooth muscle muscarinic receptor stimulation overcoming the de-pressed stimulating effect of endothelium-dependent relax-ing factors. In the present study, the serum L-PGDS level showed a significant correlation with the degree of LAD vasomotion but not with the CBF response induced by ACh. Also, the serum L-PGDS level did not show a significant cor-relation with coronary vasodilation induced by nitroglycerin or the increase in CBF induced by papaverine. These findings suggest that L-PGDS may not affect endothelium-indepen-dent coronary macro- and microvasomotor functions. Endo-thelial dysfunction is a hallmark and a predictor of coronary artery disease.23 Further studies are needed to elucidate the endothelium-dependent and -independent vasomotor mecha-nisms underlying the increase in the circulating L-PGDS level.

It has been shown that PGD2 not only induces endothelium-dependent vasorelaxation, but also prevents platelet aggrega-tion.3,4 Markers of the fibrinolytic system, such as the plasma levels of PAI-1 and fibrinopeptide A, showed circadian varia-tion in parallel with attacks of coronary spasm.24,25 Endoge-nous PGD2 decreases PAI-1 mRNA expression and PAI-1 synthesis in cultured bovine endothelial cells following incu-bation with interleukin-1β.26 Pharmacological or biological interventions targeting positive modulation of L-PGDS pro-duction would be a possible future strategy for preventing coronary thrombotic events, including VSA and/or acute coro-nary syndrome.

PGD2 is the precursor of the PGJ2 family. 15-Deoxy-delta 12, 14-PGJ2 (15d-PGJ2) has been identified as an endogenous ligand for a nuclear receptor, peroxisome proliferator-activated receptor γ (PPARγ).27,28 It has been shown that 15d-PGJ2 and synthetic PPARgamma ligands exert several effects on vascu-lar cells, such as antiatherogenic, antithrombogenic, antiapop-totic, and antiinflammatory effects, although doubts have been raised as to whether endogenous 15d-PGJ2 is produced in sufficient amounts to activate PPARγ.29 PGD2 may suppress inflammatory processes and maintain vascular homeostasis by functioning as antivasospastic factors. Early studies have reported that vasoactive substances derived from mast cells, such as PGD2, histamine, and leukotrienes C4 and D4, may have a role in the pathogenesis of coronary spasm.30 It has

been shown that the number of degranulated mast cells in the adventitia is increased in infarct-related coronary arteries.31 Sueda et al reported that increased thromboxane A2 and PGH2 levels lead to coronary artery constriction, and that intracoro-nary administration of a thromboxane A2 synthase inhibitor may inhibit thromboxane A2 synthesis in the coronary circu-lation, thus playing a major role in the relief of coronary spasm.32 It has been shown that patients with variant angina that is refractory to traditional vasodilator therapy respond to systemic corticosteroids.33 Further examination is required of the relationship between coronary vasospasm and vaso-active substances derived from the heart, based on autopsy findings in patients with coronary spasm.

In conclusion, the serum L-PGDS level was elevated in patients with VSA and was associated with epicardial coro-nary vasomotion in response to ACh. Measurement of serum L-PGDS level might be useful for screening patients for coro-nary artery disease prior to coronary angiography.

Study LimitationsWe evaluated only the changes in vessel diameter and blood flow velocity, using quantitative coronary angiography and Doppler flow guidewire analysis. Assessment of the plaque area or plaque volume by intravascular ultrasound would have provided more information about the relation between L-PGDS and coronary organic alterations. In addition, further studies are needed to examine whether or not the L-PGDS level is elevated when anginal attacks induced by coronary vasospasm are frequent.

AcknowledgmentThis study was supported in part by a Grant-in-Aid for Scientific Re-search 17590726 from the Ministry of Education, Science, and Culture, Tokyo, Japan.

DisclosureWe have no any commercial associations that might pose a conflict of interest in connection with this submitted article.

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