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

Impaired endothelium-dependent vasorelaxation (EDVR) is observed in hypercholesterolemia both in the presence and absence of morphological abnormalities and may be due to superoxide anions. Our aim was to assess the effect of gene transfer of manganese superoxide dismutase (MnSOD) to blood vessels from hypercholesterolemic animals with and without atherosclerotic plaque and to compare the effects of endothelial nitric oxide synthase (eNOS) and MnSOD over-expression on vascular dysfunction in the setting of atherosclerosis. Rabbits received a high-cholesterol diet for 10 weeks, resulting in abnormal EDVR in the absence of plaque in the carotids and the presence of plaque in the aorta. In Group 1, adenoviral vectors encoding MnSOD (AdMnSOD) or beta-galactosidase (Ad(beta)gal) were delivered to the carotid arteries in vivo. Four days later, transgene expression and vascular reactivity were assessed. In Group 2, segments of the aorta were transduced ex vivo with AdMnSOD, AdeNOS or both. Transgene expression and vascular reactivity were assessed 24 hr later. In Group 1, MnSOD expression was detected in AdMnSOD-ransduced vessels and impaired EDVR was reversed in the absence of atherosclerotic plaque. In Group 2 (with atherosclerotic plaque present), MnSOD and eNOS expression were detected by western analysis, and eNOS, but not MnSOD over-expression, improved EDVR whereas simultaneous over-expression of eNOS and MnSOD was no better than eNOS alone. Adenovirus-mediated gene transfer of MnSOD to nonatherosclerotic carotid arteries, but not atherosclerotic aorta, normalizes EDVR. eNOS gene transfer improves EDVR, even in the presence of plaque.
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PMID:Gene transfer of manganese superoxide dismutase reverses vascular dysfunction in the absence but not in the presence of atherosclerotic plaque. 1148 32

To identify the residues in the carboxyl-terminal region 260-299 of human apolipoprotein E (apoE) that contribute to hypertriglyceridemia, two sets of conserved, hydrophobic amino acids between residues 261 and 283 were mutated to alanines, and recombinant adenoviruses expressing these apoE mutants were generated. Adenovirus-mediated gene transfer of apoE4-mut1 (apoE4 (L261A, W264A, F265A, L268A, V269A)) in apoE-deficient mice (apoE(-/-)) corrected plasma cholesterol levels and did not cause hypertriglyceridemia. In contrast, gene transfer of apoE4-mut2 (apoE4 (W276A, L279A, V280A, V283A)) did not correct hypercholesterolemia and induced mild hypertriglyceridemia. ApoE-induced hyperlipidemia was corrected by co-infection with a recombinant adenovirus expressing human lipoprotein lipase. Both apoE4 mutants caused only a small increase in hepatic very low density lipoprotein-triglyceride secretion. Density gradient ultracentrifugation analysis of plasma and electron microscopy showed that wild-type apoE4 and apoE4-mut2 displaced apoA-I from the high density lipoprotein (HDL) region and promoted the formation of discoidal HDL, whereas the apoE4-mut1 did not displace apoA-I from HDL and promoted the formation of spherical HDL. The findings indicate that residues Leu-261, Trp-264, Phe-265, Leu-268, and Val-269 of apoE are responsible for hypertriglyceridemia and also interfere with the formation of HDL. Substitutions of these residues by alanine provide a recombinant apoE form with improved biological functions.
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PMID:Generation of a recombinant apolipoprotein E variant with improved biological functions: hydrophobic residues (LEU-261, TRP-264, PHE-265, LEU-268, VAL-269) of apoE can account for the apoE-induced hypertriglyceridemia. 1557 62

The objective of this study was to determine the effect of two amino-terminal apolipoprotein A-I (apoA-I) deletions on high-density lipoprotein (HDL) biosynthesis and lipid homeostasis. Adenovirus-mediated gene transfer showed that the apoA-I[Delta(89-99)] deletion mutant caused hypercholesterolemia, characterized by increased plasma cholesterol and phospholipids, that were distributed in the very low density/intermediate density/low-density lipoprotein (VLDL/IDL/LDL) region, and normal triglycerides. The capacity of the mutant protein to promote ATP-binding cassette transporter A1- (ABCA1-) mediated cholesterol efflux and to activate lecithin:cholesterol acyltranserase (LCAT) was approximately 70-80% of the wild-type (WT) control. The phospholipid transfer protein (PLTP) activity of plasma containing the apoA-I[Delta(89-99)] mutant was decreased to 32% of the WT control. Similar analysis showed that the apoA-I[Delta(62-78)] deletion mutant in apoA-I-deficient mice caused combined hyperlipidemia characterized by increased triglycerides, cholesterol, and phospholipids in the VLDL/IDL region. There was enrichment of the VLDL/IDL with mutant apoA-I that resulted in reduction of in vitro lipolysis. The capacity of this mutant to promote ABCA1-mediated cholesterol efflux was normal, and the capacity to activate LCAT in vitro was reduced by 53%. The WT apoA-I and the apoA-I[Delta(62-78)] mutant formed spherical HDL particles, whereas the apoA-I[Delta(89-99)] mutant formed discoidal HDL particles. We conclude that alterations in apoA-I not only may have adverse effects on HDL biosynthesis but also may promote dyslipidemia due to interference of the apoA-I mutants on the overall cholesterol and triglycerides homeostasis.
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PMID:Deletions of helices 2 and 3 of human apoA-I are associated with severe dyslipidemia following adenovirus-mediated gene transfer in apoA-I-deficient mice. 1575 88

PTEN is a dual-specificity phosphatase that has been shown to inhibit vascular smooth muscle cell (VSMC) proliferation and migration, two key events in the ethiopathogenesis of atherosclerosis. Adenovirus-mediated PTEN overexpression inhibited the formation of vascular obstructive lesions induced by mechanical injury of the vessel wall. In this study, we investigated whether PTEN protects against atheroma formation in apolipoprotein E-null mice (apoE-/-), a widely used animal model characterized by the development of hypercholesterolemia and atherosclerosis. We examined atheroma development in the aorta of apoE-/- mice with an intact Pten gene and apoE-/- mice lacking one allele of Pten (Pten(+/-)apoE-/-) that were challenged for six weeks with an atherogenic diet. Compared with apoE-/- controls, Western blot analysis of arterial cell lysates from Pten(+/-)apoE-/- mice revealed a decrease in PTEN expression. This correlated with increased phosphorylation of AKT, thus demonstrating that Pten inactivation in Pten(+/-)apoE-/- mice has functional consequences. However, the extent of atherosclerosis was undistinguishable in both groups of fat-fed mice. Likewise, the atheroma of Pten(+/-)apoE-/- and apoE-/- mice displayed similar VSMC content, cellularity and rates of proliferation and apoptosis. Thus, in spite of the cytostatic and antimigratory activities of PTEN, and in contrast to previous studies demonstrating that Pten is haplo-insufficient for tumor suppression, our results demonstrate that atherosclerosis in hypercholesterolemic mice is not aggravated by partial inactivation of Pten.
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PMID:Atheroma development in apolipoprotein E-null mice is not affected by partial inactivation of PTEN. 1672 Mar 46