Estrogen-mediated increases in LDL cholesterol and foam cell-containing lesions in human ApoB100xCETP transgenic mice.

The murine double transgenic mouse expressing both human apoB100 and cholesteryl ester transfer protein (CETP), has been used as a model to understand the effects mediated by various therapeutic modalities on serum lipoproteins and on atherosclerotic lesion progression. In the present study the effects of estrogen therapy on serum lipoproteins were investigated after mice were placed on an atherosclerotic diet. The daily oral administration of 20 or 100 microg/kg of 17 alpha-ethinyl estradiol resulted in a significant, dose-dependent increase in LDL cholesterol over a 20-week regimen.

Inhibition of neutrophil oxidative burst and granule secretion by wortmannin: potential role of MAP kinase and renaturable kinases.

Exposure of neutrophils to a variety of agonists including soluble chemoattractant peptides and cytokines results in degranulation and activation of the oxidative burst (effector functions) that are required for bacterial killing. At present, the signaling pathways regulating these important functions are incompletely characterized. Mitogen-activated protein (MAP) kinases (MAPK) as well as members of a family of "renaturable kinases" are rapidly activated in neutrophils in response to diverse physiological agonists, suggesting that they may regulate cell activation.

Activated recombinant human protein C does not attenuate recruitment of neutrophils in rat models of acute inflammation.

It has been proposed that the reduction in mortality in animal models of sepsis by activated protein C (APC) is mediated by an antiinflammatory property rather than the well-characterized anticoagulant action. Human recombinant APC was examined for potential antiinflammatory activity in the pentobarbital-anesthetized rat. In the dermal reversed passive Arthus model, APC (20.

Investigation of neutrophil signal transduction using a specific inhibitor of phosphatidylinositol 3-kinase.

Neutrophils contain a multicomponent NADPH oxidase system that is involved in the production of microbicidal oxidants. Stimulation of human neutrophils with the peptide FMLP activates this respiratory burst enzyme to produce superoxide and also has been shown to result in activation of phosphatidylinositol (Ptdlns) 3-kinase. Treatment of human neutrophils with 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), a potent and specific inhibitor of Ptdlns 3-kinase, resulted in complete inhibition of Ptdlns 3-kinase activity as well as in inhibition of superoxide production in FMLP-treated neutrophils in suspension; FMLP-stimulated oxidant production in adherent cells was also abolished.

Effect of activation of ATP-dependent potassium channels with (-)-pinacidil and (-)-3-pyridyl pinacidil on infarct size in a canine model of ischemia-reperfusion injury.

We tested the hypothesis that opening myocardial ATP-dependent K+ (ATP-K) channels by administration of (-)-pinacidil or (-)-3-pyridyl pinacidil intracoronarily (i.c.) either during ischemia or as pretreatment could decrease infarct size in a canine model of ischemia-reperfusion injury in anesthetized male hounds subjected to 90-min left circumflex coronary artery (LCX) occlusion followed by 5-h reperfusion.