Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Modifications by atherosclerosis of endothelium-dependent and -independent relaxations were evaluated in carotid arteries isolated from Watanabe heritable hyperlipidemic (WHHL; age 20-29 months) and age-matched Japanese white (JW) rabbits. Marked, patchy atherosclerotic lesions were observed in all WHHL rabbit arteries. Endothelium-dependent relaxations induced by acetylcholine, partly depressed by N(G)-nitro-L-arginine (L-NA), were significantly inhibited in the WHHL rabbit arteries with atherosclerosis, compared with those in the arteries without atherosclerotic lesions from JW and WHHL rabbits. No difference was observed in the relaxation caused by superoxide dismutase in these arteries. Conversely, endothelium-dependent relaxations by substance P were greater in the arteries with and without atherosclerosis from WHHL rabbits than in the arteries from JW rabbits. Endothelium-independent relaxations elicited by sodium nitroprusside and 2,2-(hydroxynitrosohydrazino)bis-ethanamine (NOC18) did not differ in the arteries from JW and WHHL rabbits. The responses to acetylcholine and substance P of JW rabbit arteries with the endothelium were not attenuated by treatment with pertussis toxin. L-NA-resistant, endothelium-dependent relaxations by substance P were almost abolished by charybdotoxin, and atherosclerosis did not alter the response. It is concluded that endothelial functions, evaluated by substance P, in rabbit carotid arteries are not impaired by atherosclerosis and by long exposure to hyperlipidemia in vivo. Dysfunction of muscarinic receptors may be involved in the depressed response to acetylcholine. As far as the arteries used in the present study are concerned, responses mediated possibly by endothelium-derived hyperpolarizing factor (EDHF) are unlikely to be modulated by atherosclerosis.
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PMID:Comparison of endothelium-dependent relaxation in carotid arteries from Japanese white and Watanabe heritable hyperlipidemic rabbits. 1106 23

We present evidence of a link between low-density lipoprotein (LDL) receptor binding and activation of a platelet G-coupled protein. LDL stimulation induced cytosolic [Ca2+]i mobilization, increase in inositol 1,4,5-triphosphate (IP3) formation and a rapid cytosol-to-membrane translocation of protein kinase C (PKC) enzymatic activity. Pertussis toxin inhibited all the stimulatory effects, whereas cholera toxin had no effect. Using ligand-binding assays, we demonstrated that exposing platelet LDL receptors to high concentrations of LDL (1.5 g/l) caused a rapid down-regulation and desensitization, as shown by the reduction in the Bmax, intracellular [Ca2+]i mobilization and IP3 formation to 65, 73 and 63%, respectively. The inhibitory effects were reversible and dose and time dependent. Furthermore, VLDL (0.2 g/l) and IDL (0.07 g/l) induced similar desensitization effects. However, HDL3 (up to 1.5 g/l), chylomicrons (up to 0.5 g/l) and cyclohexandione-modified LDL (which does not bind to platelets) had no significant effects. Protein kinase C inhibitors (150 nmol/l staurosporine, 100 micromol/l H-7, and 10 nmol/l bisindolylmaleimide) inhibited desensitization to 71%, on average. Sequestration blocking agents (0.30 g/l, concanavalin A) had no significant effect if phosphorylation was operative. However, there was a complete blockade with the concurrent inhibition of both pathways. In contrast, cAMP-dependent protein kinase inhibitors (PKI, 1 micromol/l) or beta2-adrenergic receptor kinase inhibitors (100 nmol/l, heparin), had no effect. Overall results indicate that LDL binds to a pertussis sensitive G-protein coupled receptor and that high levels of lipoproteins down-regulate the number of receptors and desensitize its mediated response by a mechanism that involves PKC-phosphorylation and sequestration of binding sites. This new regulatory mechanism may have implications for the thrombogenicity in hyperlipidemia and for effects of lipid lowering therapy.
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PMID:Low-density lipoprotein (LDL) binds to a G-protein coupled receptor in human platelets. Evidence that the proaggregatory effect induced by LDL is modulated by down-regulation of binding sites and desensitization of its mediated signaling. 1122 31

Monocytes are heterogeneous effector cells involved in the maintenance and restoration of tissue integrity. However, their response to hyperlipidemia remains poorly understood. Here, we report that in the presence of elevated levels of triglyceride-rich lipoproteins, induced by administration of poloxamer 407, the blood numbers of non-classical Ly6C/Gr1(low) monocytes drop, while the number of bone marrow progenitors remains similar. We observed an increased crawling and retention of the Gr1(low) monocytes at the endothelial interface and a marked accumulation of CD68(+) macrophages in several organs. Hypertriglyceridemia was accompanied by an increased expression of tissue, and plasma CCL4 and blood Gr1(low) monocyte depletion involved a pertussis-toxin-sensitive receptor axis. Collectively, these findings demonstrate that a triglyceride-rich environment can alter blood monocyte distribution, promoting the extravasation of Gr1(low) cells. The behavior of these cells in response to dyslipidemia highlights the significant impact that high levels of triglyceride-rich lipoproteins may have on innate immune cells.
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PMID:Triglyceride-Rich Lipoproteins Modulate the Distribution and Extravasation of Ly6C/Gr1(low) Monocytes. 2634 69