Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001486 (Adenovirus)
 3,125 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lipoprotein lipase (LPL) is the rate-limiting enzyme for the hydrolysis of triglyceride-rich lipoproteins. We tested the efficacy of adenovirus-mediated gene transfer of LPL as treatment of experimental hyperlipidemias associated with apolipoprotein (apoE) deficiency (apoE-/-) and low-density lipoprotein receptor (LDLr) deficiency (LDLr-/-) in mice. Replication-defective adenovirus containing the human LPL cDNA driven by a cytomegalovirus promoter (Ad.hLPL) efficiently transduced CHO-ldlA7 cells in vitro, inducing in these cells the production of bioactive LPL (73 mU/ml). Intravenous injection of Ad.hLPL (2 x 10(9) pfu) led to high-level expression of hLPL mRNA and LPL activity in the liver (88.3 mU/ml) and in post-heparin plasma (116.1 mU/ml). Overexpression of LPL resulted in marked reductions in total plasma cholesterol (TC; 48%, 43%, 25%) and triglycerides (TTg; 63%, 40%, 70%, p < 0.01) in apoE-/-, LDLr-/-, and wild-type (WT) mice, respectively. Fast protein liquid chromatography (FPLC) fractionation of plasma lipoproteins showed a marked decrease in very-low-density lipoprotein (VLDL)/chylomicron remnant cholesterol (V/CR-C) in apoE-/- (83%), LDLr-/- (84%), and WT mice (58%, p < 0.01). VLDL/chylomicron remnant triglycerides (V/CR-Tg) were virtually eliminated in apoE-/- (92%), LDLr-/- (86%), and WT mice (84%, p < 0.05). No significant changes were detected in LPL activities, plasma lipids, or lipoproteins of mice injected with a control virus, Ad.Luc, containing the luciferase instead of the LPL cDNA. In summary, infusion of Ad.hLPL leads to increased liver and post-heparin plasma LPL activities, significantly reduced TC, TTg, V/CR-C, and V/CR-Tg in WT mice, as well as in mice with apoE and LDLr deficiencies. Adenovirus-mediated LPL gene transfer to the liver is an effective means of reversing many of the lipoprotein abnormalities in apoE- and LDLr-deficient mice.
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PMID:Adenovirus-mediated gene transfer of human lipoprotein lipase ameliorates the hyperlipidemias associated with apolipoprotein E and LDL receptor deficiencies in mice. 938 58

It has been established that low-density lipoprotein receptor-related protein (LRP) is involved in the cellular uptake and degradation of coagulation factor VIII (FVIII) in vitro. To address the physiologic role of LRP in regulating plasma FVIII in vivo, we used cre/loxP-mediated conditional LRP- deficient mice (MX1cre(+)LRP(flox/flox)). Upon inactivation of the LRP gene, MX1cre(+)LRP(flox/flox) mice had significantly higher plasma FVIII as compared with control LRP(flox/flox) mice (3.4 and 2.0 U/mL, respectively; P <.001). Elevated plasma FVIII levels in MX1cre(+)LRP(flox/flox) mice coincided with increased plasma von Willebrand factor (VWF) (2.0 and 1.6 U/mL for MX1cre(+)LRP(flox/flox) and control LRP(flox/flox) mice, respectively; P <.05). Elevation of plasma FVIII and VWF persisted for at least 6 weeks after inactivation of the LRP gene. Upon comparing plasma FVIII and VWF in individual mice, we observed an increase of the FVIII/VWF ratio in MX1cre(+)LRP(flox/flox) mice as compared with control LRP(flox/flox) mice. Administration of either a vasopressin analog or an endotoxin resulted in increased plasma VWF, but not FVIII. In clearance experiments, MX1cre(+)LRP(flox/flox) mice displayed a 1.5-fold prolongation of FVIII mean residence time. Adenovirus-mediated overexpression of the 39-kDa receptor-associated protein (RAP) in normal mice resulted in a 3.5-fold increase of plasma FVIII. These data confirm that the regulation of plasma FVIII in vivo involves a RAP-sensitive mechanism. Surprisingly, plasma FVIII in MX1cre(+)LRP(flox/flox) mice increased 2-fold after RAP gene transfer. We propose that RAP-sensitive determinants other than hepatic LRP contribute to the regulation of plasma FVIII in vivo.
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PMID:Elevated plasma factor VIII in a mouse model of low-density lipoprotein receptor-related protein deficiency. 1252 8

Low-density lipoprotein receptor-related protein (LRP) contributes to factor VIII (FVIII) catabolism in vivo. Besides LRP, FVIII also interacts with very low-density lipoprotein receptor (VLDLR) in vitro. We investigated the physiological role of VLDLR in FVIII catabolism, using knockout mouse models for VLDLR and LRP, alone and in combination. VLDLR(-/-) mice displayed normal plasma FVIII, whereas VLDLR(-/-) LRP(-) double-knockout mice had slightly increased FVIII compared with LRP-deficient mice. Remarkably, VLDLR deficiency slightly accelerated FVIII clearance. Adenovirus-mediated overexpression of VLDLR did not lower plasma FVIII in LRP-deficient mice. We conclude that VLDLR does not act in concert with LRP in FVIII clearance in vivo.
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PMID:Clearance of coagulation factor VIII in very low-density lipoprotein receptor knockout mice. 1532 26