Expression and Cellular Localization of 15-Hydroxy-Prostaglandin-Dehydrogenase in Abdominal Aortic Aneurysm

Abstract

PGE2 has been implicated in abdominal aortic aneurysm (AAA) associated hypervascularization. PGE2-metabolism involves 15-hydroxyprostaglandin-dehydrogenase (15-PGDH) the expression of which in AAA is unknown. The aim of this study was to examine the expression and cell distribution of 15-PGDH in AAA. Here, we show that 15-PGDH mRNA levels were significantly higher in aorta samples from patients undergoing AAA repair than in those from healthy multiorgan donors. Consequently, the ratio of metabolized PGE2 secreted by aortic samples was significantly higher in AAA. AAA production of total PGE2 and PGE2 metabolites correlated positively with PGI2 production, while the percentage of metabolized PGE2 correlated negatively with the total amount of PGE2 and with PGI2. Transcript levels of 15-PGDH were statistically associated with leukocyte markers but did not correlate with microvascular endothelial cell markers. Immunohistochemistry revealed 15-PGDH in the areas of leukocyte infiltration in AAA samples, mainly associated with CD45-positive cells, but not in normal aorta samples. We provide new data concerning 15-PGDH expression in human AAA, showing that 15-PGDH is upregulated in AAA and mainly expressed in infiltrating leukocytes. Our data suggest that microvasculature was not involved in PGE2 catabolism, reinforcing the potential role of microvasculature derived PGE2 in AAA-associated hypervascularization.

Fig 1. The expression of PGE₂ biosynthetic and catabolic enzymes is increased in AAA.

A, Box plot of expression levels of COX-2, mPGES-1 and 15-PGDH in controls (NA, n = 15) and abdominal aortic aneurysm (AAA, n = 39) samples; * p<0.05, when compared with NA samples. B, Box plot of the percentage of metabolized PGE₂ (MPGE₂) in NA (n = 12) and AAA (n = 30) samples; * p<0.01, when compared with NA samples.

Fig 2. 15-PGDH expression is associated with leukocyte markers in AAA.

A, Box plot of expression levels of cell markers in controls (NA, n = 15) and abdominal aortic aneurysm (AAA, n = 39) samples; * p<0.05, *** p<0.001 when compared with NA samples. B Statistical correlations between transcript levels of 15-PGDH and endothelial cell markers in AAA samples; C, statistical correlations between transcript levels of 15-PGDH and leukocyte markers in AAA samples. Pearson Product Moment Correlation after logarithmic transformation of data and Bonferroni’s correction for multiple testing was applied; (n = 39.)

Fig 3. PGE₂ production is associated with PGI₂-producing cells.

A, Statistical correlation between levels of 6-oxo-PGF_1α and total PGE₂ secreted by AAA samples; B, statistical correlation between levels of 6-oxo-PGF_1α and PGE₂ metabolites (MPGE₂) secreted by AAA samples. C, Statistical correlation between the percentage of metabolized PGE₂ secreted by AAA samples [%MPGE2; (MPGE₂/totalPGE₂)*100] and total PGE₂; D, statistical correlation between secreted levels of 6-oxo-PGF_1α and %MPGE₂. Pearson Product Moment Correlation after logarithmic transformation of data and Bonferroni’s correction for multiple testing was applied; (n = 30).

Fig 4. 15-PGDH expression in AAA is mainly associated to CD45 cells.

A, Representative immunohistochemistry images of 15-PGDH in NA and AAA samples, arrows show medial leukocyte immunostained with anti-15-PGDH; bars are 200μm (upper panels) and 50μm (lower panels). B, Representative immunofluorescent double staining for 15-PGDH and leukocyte markers in leukocyte infiltration areas; arrows show double immunostained cells; M indicates the light of microvessels; bars are 25μm.