Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Octimibate, 8-[(1,4,5-triphenyl-1H-imidazol-2-yl)oxy]octanoic acid, is reported to have antithrombotic properties. This is in addition to its antihyperlipidaemic effects which are due to inhibition of acylCoA:cholesterol acyltransferase (ACAT). The aim of this study was to investigate the mechanism of the antithrombotic effect of octimibate, and to determine whether the effects of octimibate are mediated through prostacyclin receptors. 2. In suspensions of washed (plasma-free) human platelets, octimibate is a potent inhibitor of aggregation; its IC50 is approx. 10 nM for inhibition of aggregation stimulated by several different agonists, including U46619 and ADP. The inhibitory effects of octimibate on aggregation are not competitive with the stimulatory agonist; the maximal response is suppressed but there is no obvious shift in potency of the agonist. In platelet-rich plasma, octimibate inhibits agonist-stimulated aggregation with an IC50 of approx. 200 nM. 3. Octimibate also inhibits agonist-stimulated rises in the cytosolic free calcium concentration, [Ca2+]i, in platelets. Both Ca2+ influx and release from intracellular stores are inhibited. The effects of octimibate on aggregation and [Ca2+]i are typical of agents that act via elevation of adenosine 3':5'-cyclic monophosphate (cyclic AMP). Similar effects are seen with forskolin, prostacyclin (PGl2) and iloprost (a stable PGl2 mimetic). 4. Octimibate increases cyclic AMP concentrations in platelets and increases the cyclic AMP-dependent protein kinase activity ratio. Octimibate stimulates adenylyl cyclase activity in human platelet membranes, with an EC50 of 200 nM. The maximal achievable activation of adenylyl cyclase by octimibate is 60% of that obtainable with iloprost. Octimibate has no effect on the cyclic GMP-inhibited phosphodiesterase (phosphodiesterase-ITI), which is the major cyclic AMP-degrading enzyme in human platelets.5. Octimibate inhibits, apparently competitively, the binding of [3H]-iloprost (a stable PGl2 mimetic) to platelet membranes; the estimated Ki is 150 nm. 6. The platelets of different species show considerable differences in the apparent potency of their inhibition of aggregation by octimibate; platelets from cynomolgus monkeys are 3 fold more sensitive than those from humans, while rat, cat and cow platelets are 50, 100, and 250 fold less sensitive than human platelets. The sensitivity of these different species to iloprost, however, varies over a range of only 10 fold with no obvious difference between primates and non-primates. 7. Octimibate appears to be a potent agonist (aggregation), or partial agonist (adenylyl cyclase), at prostacyclin receptors and is the first non-prostanoid agent of this type to be identified. The species differences in relative potency of octimibate and iloprost may reflect the existence of receptor subtypes.
 ...
PMID:Octimibate, a potent non-prostanoid inhibitor of platelet aggregation, acts via the prostacyclin receptor. 171 May 26

Lysosomal accumulation of unesterified (free) cholesterol, following the phagocytic incorporation of cholesteryl oleate lipid droplets, was quantitatively characterized in a murine J774 macrophage foam cell model. The induction of phagocytic incorporation by the macrophages, using an inverted culture technique, allowed the rapid delivery of large amounts of cholesteryl ester droplets to the lysosomes, leading to the subsequent generation of free cholesterol. The lysosomally generated free cholesterol was differentiated from the membrane cholesterol by a double radiolabeling procedure. Free cholesterol accumulation was quantitated in a population of low density lipid-filled lysosomes prepared by ultracentrifugal isolation of a floating lipid fraction from a homogenate of the cholesteryl ester-loaded cells. About 10% of the total N-acetyl-beta-glucosaminidase activity, a lysosomal marker, was recovered in the lipid fraction. Negligible amounts of alkaline phosphodiesterase-1, a plasma membrane marker, or membrane cholesterol were present in this fraction. Electron microscopic and cytochemical analysis of the isolated lipid fraction revealed the presence of lysosomes in the fraction with a diameter ranging from 1.5 to 4 microns. Continued hydrolysis of incorporated cholesteryl ester over a 24-h incubation resulted in approximately 30% of the generated free cholesterol in lipid-filled lysosomes. The accumulation of free cholesterol occurred whether or not the cholesterol esterifying enzyme, acyl-CoA: cholesterol acyltransferase, was inhibited. In addition, substantial amounts of free cholesterol accumulated even in the presence of efficient cholesterol acceptor particles, apolipoprotein high density lipoprotein-phosphatidylcholine complexes which stimulate cholesterol efflux. Also, increased accumulation of free cholesterol in the lipid fraction was observed when cholesteryl ester-loaded cells were treated with the compound U-18666A which blocks the movement of lysosomal cholesterol. The data demonstrate that the phagocytic incorporation and hydrolysis of cholesteryl ester lipid droplets by macrophage foam cells lead to a substantial accumulation of free cholesterol in the lipid-filled lysosomes. This process could result in a build-up of lysosomal free cholesterol in macrophage foam cells during the progression of atherosclerotic plaque.
 ...
PMID:Lysosomal accumulation of unesterified cholesterol in model macrophage foam cells. 848 53