Lipocalin-type prostaglandin D synthase is a powerful biomarker for severity of stable coronary artery disease
Introduction
Prostaglandin (PG) D2 is one of the metabolites of PGH2, which is a common precursor in the synthesis of various prostanoids derived from arachidonic acid [1], [2]. PGD2 is produced in various tissues and cells and has various physiological actions including the regulation of sleep [3] and nociception [4], inhibition of platelet aggregation [5], and induction of vasodilatation and bronchoconstriction [6]. Lipocalin-type PGD synthase (L-PGDS) [7] is one of the enzymes involved in the biosynthesis of PGD2, as it catalyzes the isomerization of PGH2 to PGD2[2]. 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 [8], [9]. L-PGDS was identified in autopsy specimens of atherosclerotic plaques of human coronary arteries and found to be secreted into the bloodstream [10]. In addition, an enzyme-linked immunosorbent assay (ELISA) for L-PGDS has been established to determine its serum levels [11], [12].
The purpose of this multicenter cooperative study was to assess the significance of serum L-PGDS level as a clinical indicator of stable coronary artery disease. Prior to the study, we observed the immunoreactivity and mRNA expression of L-PGDS to confirm that L-PGDS was definitely localized and generated in atherosclerotic plaques, especially of the human coronary artery.
Section snippets
Localization and mRNA expression of L-PGDS
We obtained atherosclerotic tissues of aorta and carotid, internal mammary, iliac and coronary arteries from 3 autopsy cases (2 males and 1 female), who died of non-cardiovasular causes. These cases had moderate atherosclerosis in these arteries, although there were no symptoms of atherosclerotic coronary artery disease, cerebrovascular disease, or peripheral artery disease. Immediately after the arteries were removed, the tissues were fixed with 4% paraformaldehyde in sodium phosphate at 4 °C
Immunohistochemistry and RT-PCR
Using immunostaining of the autopsy specimens, we observed the immunoreactivity for L-PGDS in the atherosclerotic plaque of the internal mammary, carotid, and coronary arteries. More intense immunoreactivity for L-PGDS was detected in the atherosclerotic plaque of the coronary artery than in that of the internal mammary artery or common iliac artery (Fig. 1, A). The L-PGDS-positive cells were neointimal as well as medial smooth muscle cells. RT-PCR showed amplified cDNA from mRNA encoding
Discussion
The major findings of our multicenter study are that serum L-PGDS level was elevated in patients with stable coronary artery disease and that the level increased in association with the number of affected vessels. In addition, our simple or multiple regression analyses shows that the L-PGDS level could predict the Gensini score, which indicates lesion severity for the entire coronary artery system. These results suggest that the L-PGDS level may be suitable as a biomarker of atherosclerotic
Acknowledgements
We thank the patients who volunteered for this study. This work was supported in part by grants from the Corporated Technology Development Program of the Japan Science and Technology Corporation, the program Grants-in-Aid for Scientific Research of the Ministry of Education, Culture, Sports, Science and Technology, the Japanese Government (No. 12558078 to Y.U.), the Takeda Science Foundation (to Y.U.), and Osaka City.
Participants: M. Shimizu (Department of Cardiology, Koshigaya Hospital, Dokkyo
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For the PGDS Heart Study Group.