Prostacyclin modulates cholesteryl ester hydrolytic activity by its effect on cyclic adenosine monophosphate in rabbit aortic smooth muscle cells.

Abstract

A B S T R A C T We tested the hypothesis that prostacyclin (PGI2), 6-keto-prostaglandinF,,,(6-keto-PGF,a), and several E series prostaglandins (PG) may affect the activity of cholesteryl ester (CE) hydrolase since our previous experiments indicated that smooth muscle cells (SMC) in neointima of injured rabbit aorta (a) acquire the capacity to produce PGI2 and (b) have increased lysosomal CE hydrolytic (acid cholesteryl ester hydrolase [ACEH])activity. Using cultured SMC from rabbit thoracic aorta, we demonstrated that PGI2, 6-keto-PGF1,, and 6-keto-PGE, enhanced ACEH activity fourfold. No significant effects on ACEH activity were observed with PGE1 or PGE2. Preincubation of SMC with an inhibitor of adenylate cyclase activity (dideoxyadenosine) abolished the effect of these PG on CE hydrolytic activity. Addition of dibutyryl cAMP to these SMC significantly increased ACEH activity.Although concentrations of PGI2 used significantly increased cAMP levels, proliferation of these SMC was not observed.In related experiments, we determined if the addition of PGI2, 6-keto-PGF,a, or 6-keto-PGE1 to cultured aortic SMC would enhance the egress of unesterified cholesterol and CE from these SMC. A significant loss of total cholesterol. from PG-treated SMC Parts of this study were presented at a meeting of the Federation of

Regulation of vascular prostaglandin synthesis by metabolites of arachidonic acid in perfused rabbit aorta.

“…To compare the metabolic effects of endogenously released arachidonic acid with those of exogenously added arachidonate we infused ionophore A23187, 4 MM, into five aortas (Fig. 7).…”

“…These results are similar to those of Hemler et al (19), who found potentiation of cyclooxygenase activity in a purified enzyme preparation by various peroxides in the range of 0 to 2 MM. In general, PGE2 does not have the potent vasodilatory or antiplatelet effects of PGI2 (41)(42)(43), and in the example of cholesterol ester hydrolytic activity, is inactive (4). Thus, despite increased cyclooxygenase activity due to enhanced "peroxide tone," arachidonic acid metabolism is diverted to biologically less active or inactive products as cyclic endoperoxides are diverted away from inactivated prostacyclin synthetase.…”

“…The INTRODUCTION Vascular endothelium synthesizes prostacyclin (PGI2),l an extremely potent vasodilator and platelet antiaggregatory agent. Synthesis of PGI2 by blood vessels is an important component in a number of vascular functions including the thromboresistance of the intact vascular surface (1), the recovery of thromboresistance and limitation of platelet aggregation after vascular injury (2), the inhibition of vascular smooth muscle proliferation (3), and the modulation of cholesterol ester hydrolase activity and cholesterol egress from cultured smooth muscle cells (4). In addition, prostaglandin (PG) (probably PGI2) synthesis by the vascular endothelium plays an important role in the full hemodynamic effect of many clinically used vasoactive drugs (5)(6)(7)(8), and is involved in the vascular response to endogenous vasoactive agents (9)(10)(11).…”

Altered brain lipid composition in cyclooxygenase-2 knockout mouse

“…The reduction in this ratio would be expected to increase membrane fluidity (40). The reduction was not related to a reduced brain CerPCho concentration (Tables 1, 3), which can alter cholesterol concentration (41,42), but may have been related to reduced COX-2-derived metabolites such as prostacyclin, because prostacyclin was reported to enhance neutral and acid cholesteryl ester hydrolase activity in aortic smooth muscle cells (43). The nonnormalized concentration of palmitic acid was decreased significantly in cholesteryl ester.…”

The sterol response element binding protein regulates cyclooxygenase-2 gene expression in endothelial cells

“…There is evidence to suggest a reciprocal role for prostaglandins in intracellular cholesterol homeostasis. Prostacyclin has been shown to enhance neutral and acid cholesteryl ester hydrolase activity in aortic smooth muscle cells (41,42). The cholesterol-sensitive SREBP is activated when intracellular stores of cholesterol are depleted, linking PGI 2 production and cholesterol homeostasis.…”