Platelet-neutrophil-smooth muscle cell interactions: lipoxygenase-derived mono- and dihydroxy acids activate cholesteryl ester hydrolysis by the cyclic AMP dependent protein kinase cascade.
Fluid-phase interactions between hematologic cells and those of the vessel wall were studied in order to define a role for lipoxygenase products as cell signals in the control of vascular cholesterol metabolism. A functional parameter for hydroxy acids in this system has not been previously demonstrated. We report herein for the first time a biochemical effect of lipoxygenase-derived eicosanoids in the modulation of cholesterol metabolism in smooth muscle cells. Products of platelet-neutrophil interactions served as cell signals in vitro to modulate cholesterol metabolism. We demonstrate that 12-HETE, 12,20-DiHETE, and 12-HETE-1,20-dioic acid activate both lysosomal and cytoplasmic cholesteryl ester (CE) hydrolytic activities, although no effect was observed on CE synthetic (ACAT) activity. The platelet lipoxygenase product, 12-HETE, was the most effective stimulator of CE hydrolysis in the smooth muscle cell, and its conversion to 12,20-DiHETE and the dioic acid derivative by the neutrophils was not necessary for the activation of CE hydrolase. A 2-fold enhancement on CE hydrolysis occurred and was independent of any "cross-activation" by hydroxy acids on production of cyclooxygenase or other lipoxygenase products. The activation of cytoplasmic CE hydrolysis had a lesser cofactor dependence on bile salts in the presence of 12-HETE. This suggested a reduced requirement for surface-active agents in an enzyme-substrate interaction where enzymes are hydrolyzing insoluble lipid substrates. Moreover, 12-HETE induced an additive effect with several lipolytic hormones in the activation of CE catabolism.(ABSTRACT TRUNCATED AT 250 WORDS)
Hajjar
D P
DP
Department of Biochemistry, Cornell University Medical College, New York, New York 10021.
Marcus
A J
AJ
Etingin
O R
OR
D000818:Animals; D001792:Blood Platelets / Q000502:physiology*; D002417:Cattle; D002478:Cells, Cultured; D002788:Cholesterol Esters / Q000378:metabolism*; D000242:Cyclic AMP / Q000096:biosynthesis* / Q000502:physiology; D004789:Enzyme Activation; D006867:Hydrolases / Q000378:metabolism; D006868:Hydrolysis; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology*; D008084:Lipoxygenase / Q000097:blood / Q000378:metabolism; D009130:Muscle, Smooth / Q000201:enzymology / Q000502:physiology*; D009504:Neutrophils / Q000502:physiology*; D011494:Protein Kinases / Q000097:blood / Q000378:metabolism*
D002788:Cholesterol Esters; D006893:Hydroxyeicosatetraenoic Acids; D000242:Cyclic AMP; D008084:Lipoxygenase; D011494:Protein Kinases; D006867:Hydrolases