Sex Differential in 15-Hydroxyprostaglandin Dehydrogenase Levels in the Lumen of Human Intracranial Aneurysms.

BACKGROUND: Aspirin is a promising medical therapy for the prevention of intracranial aneurysm (IA) rupture. Recently, we found that men have a better response to aspirin than women. The purpose of this study was to determine whether a sex differential exists in the level of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in the lumen of human IAs. METHODS AND RESULTS: Consecutive patients undergoing coiling or stent-assisted coiling for a saccular IA at our institution were enrolled. Two samples (A and B) were collected from IA lumens, and the plasma level of 15-PGDH was measured using an ELISA-based method. The study included 38 patients, with 20 women and 18 men. Women and men were comparable on baseline characteristics. The mean plasma concentration of 15-PGDH did not differ statistically between sample A (62.8±16.2 ng/mL) and sample B (61.8±17.9 ng/mL; 95% confidence interval -6.6 to 9.4). The mean plasma concentration of 15-PGDH in IA lumens of samples A and B was significantly higher in men (73.8±13.5 ng/mL) than women (49.6±7.8 ng/mL; P<0.0001). CONCLUSIONS: Higher enzyme levels of 15-PGDH exist in the lumen of IAs of men compared with women. This observation could explain why aspirin confers better protection against IA rupture in men than in women. The susceptibility of an individual to aspirin may differ according to the level of 15-PGDH.

Prostacyclin production in vascular endothelium of patients with Blackfoot disease.

The levels of 6-keto-PGF1 alpha and TXB2 were determined by the RIA method in Blackfoot disease which is an endemic disease of the peripheral vascular system found in the southwest coast of Taiwan. The level of TXB2 was normal, but that of 6-keto-PGF2 alpha concentration was 30% lower than the normal. The activity of 15-hydroxyprostaglandin dehydrogenase was higher in patients' blood plasma than in the normal. Patient's vascular endothelium was also found to have lower prostacyclin synthase activity. These results suggest that the reduced prostacyclin production in vascular endothelium contributes to the pathogenesis of Blackfoot disease.

Platelet prostaglandin D2 dehydrogenase in patients with myeloproliferative disorders.

NADP-linked 15-hydroxyprostaglandin dehydrogenase for prostaglandin D2 (PGD2DH) transforms prostaglandin D2 (PGD2) to inactive 15-keto-PGD2. This enzyme activity was spectrophotometrically determined in the cytosol of platelets and platelet sensitivities to PGD2 were studied in patients with myeloproliferative disorders (MPD) as well as in normal subjects. Platelet sensitivities to exogenous and endogenous PGD2 were estimated by IC50 of added PGD2 for platelet aggregation and by the inhibitory effect of a specific thromboxane synthetase inhibitor (OKY-046) on collagen-induced aggregation, respectively. PGD2DH activities of MPD patients were significantly higher than those of normal subjects (p less than 0.01). Although decreased sensitivity to exogenous PGD2 was detected in some MPD patients, they were not always associated with the increased enzyme activities. Furthermore, no specific correlation was found between PGD2DH activities and the inhibitory effects of OKY-046. Thus, PGD2DH seems to have little effect on the action of PGD2 against platelet aggregation in MPD patients and normal subjects.

Prostaglandin-9-ketoreductase activity in erythrocytes of normal and hypertensive subjects.

The PGE2/PGF2 alpha balance, controlled in part by prostaglandin-9-ketoreductase, seems to be involved in the regulation of sodium excretion by the kidney. A decreased PGE2/PGF2 alpha ratio has been observed in the urine of hypertensive subjects. This suggests that an alteration of prostaglandin metabolism might be involved in the pathogenesis of essential hypertension. In order to test this hypothesis, prostaglandin-9-ketoreductase (PG-9-KR) and prostaglandin-15-dehydrogenase (PG-15-DH) activities were measured in erythrocytes of normotensive controls and patients with essential hypertension. The two enzyme activities were highly correlated in the two groups, supporting the hypothesis that they are alternate expressions of a single enzyme. These two enzyme activities were not significantly different in hypertensive subjects as compared to controls. Human essential hypertension does not appear to be linked to a generalized defect of prostaglandin catabolic enzymes.

Metabolism of prostacyclin by 9-hydroxyprostaglandin dehydrogenase in human platelets. Formation of a potent inhibitor of platelet aggregation and enzyme purification.

We have reported the identification of a metabolite of prostacyclin (PGI2) in the liver, 6-keto-PGE1, a substance having similar potency to PGI2 in its vascular and antiaggregative actions but differing in its greater stability. Either PGI2 or its inactive hydrolysis product, 6-keto-PGF1 alpha, can be enzymically transformed via the 9-hydroxyprostaglandin dehydrogenase pathway to 6-keto-PGE1. In this study, we demonstrated 9-OH prostaglandin dehydrogenase activity in the cytoplasmic fraction of human platelets by measuring the release of 3H from positin 9 using [9-3H]PGI2 and [9-3H]6-keto-PGF1 alpha as substrates. The enzyme was further purified by DEAE-cellulose, followed by Sephadex G-200, and finally by isoelectric focusing. The enzyme was found to have a pH optimum of 8.5 to 9.0 and an isoelectric point of 5.0. The molecular weight was estimated to be 60,000 by sodium dodecyl sulfate-gel electrophoresis. Enzymic activity was time- and concentration-dependent and required NAD+ as a cofactor. The activity of the purified enzyme was further confirmed by using a more stable form of PGI2, the methyl ester. Incubation of [11-3H]PGI2 methyl ester with the purified enzyme resulted in formation of [11-3H]6-keto-PGE1 methyl ester, which also inhibited platelet aggregation. Thus, 9-hydroxyprostaglandin dehydrogenase in platelets could be a major enzymic pathway for the transformation of PGI2, and perhaps 6-keto-PGF1 alpha, to 6-keto-PGE1. The possibility that the effects of prostacyclin on platelet aggregation are related to conversion to the biologically active metabolite, 6-keto-PGE1, should be considered.

Conversion of PGE2 to PGF2alpha by fetal sheep blood.

In an attempt to explain the differences in the concentration of primary prostaglandins in the circulation of adult and fetal sheep, we have examined the ability of whole blood from adult and fetal sheep to reduce PGE2 to PGF2alpha in vitro. PGF2alpha was the principal radioactive product formed from 3H PGE2 by both adult and fetal blood. The enzyme initial reaction velocity was significantly higher (P = 0.02) per ml of fetal than adult blood. The optimum enzyme pH (7.0 - 7.5) was similar for both adult and fetal blood. The Km of the enzyme in fetal and adult blood were 3.59 x 10(-7) M and 5.02 x 10(-7) M respectively (P greater than 0.05). There was no detectable metabolism of PGF2alpha by either adult or fetal sheep blood. The results indicate that prostaglandin 9-ketoreductase is present in both adult and fetal sheep blood. Differences in the activity of this enzyme are unlikely to explain the higher concentrations of PGE reported in the plasma of fetal lambs.