Search

Your search keyword '"G Lee R"' showing total 4 results
Start Over Author "G Lee R"
4 results on '"G Lee R"'

1. Predictive value of telomere length on outcome following acute myocardial infarction: Evidence for contrasting effects of vascular vs. blood oxidative stress

Author

Margaritis, M. Sanna, F. Lazaros, G. Akoumianakis, I. Patel, S. Antonopoulos, A.S. Duke, C. Herdman, L. Psarros, C. Oikonomou, E.K. Shirodaria, C. Petrou, M. Sayeed, R. Krasopoulos, G. Lee, R. Tousoulis, D. Channon, K.M. Antoniades, C.

Abstract

Aims Experimental evidence suggests that telomere length (TL) is shortened by oxidative DNA damage, reflecting biological aging. We explore the value of blood (BTL) and vascular TL (VTL) as biomarkers of systemic/vascular oxidative stress in humans and test the clinical predictive value of BTL in acute myocardial infarction (AMI). Methods and results In a prospective cohort of 290 patients surviving recent AMI, BTL measured on admission was a strong predictor of all-cause [hazard ratio (HR) [95% confidence interval (CI)]: 3.21 [1.46-7.06], P = 0.004] and cardiovascular mortality (HR [95% CI]: 3.96 [1.65-9.53], P= 0.002) 1 year after AMI (for comparisons of short vs. long BTL, as defined by a T/ S ratio cut-off of 0.916, calculated using receiver operating characteristic analysis; P adjusted for age and other predictors). To explore the biological meaning of these findings, BTL was quantified in 727 consecutive patients undergoing coronary artery bypass grafting (CABG), and superoxide (O2 .-) was measured in peripheral blood mononuclear cells (PBMNC). VTL/vascular O2 .-were quantified in saphenous vein (SV) and mammary artery (IMA) segments. Patients were genotyped for functional genetic polymorphisms in P22ph-x (activating NADPH-oxidases) and vascular smooth muscle cells (VSMC) selected by genotype were cultured from vascular tissue. Short BTL was associated with high O2 .-in PBMNC (P = 0.04) but not in vessels, whereas VTL was related to O2 .-in IMA (q =-0.49, P=0.004) and SV (q =-0.52, P= 0.01). Angiotensin II (AngII) incubation of VSMC (30 days), as a means of stimulating NADPHoxidases, increased O2 .-and reduced TL in carriers of the high-responsiveness P22ph-x alleles (P=0.007). Conclusion BTL predicts cardiovascular outcomes post-AMI, independently of age, whereas VTL is a tissue-specific (rather than a global) biomarker of vascular oxidative stress. The lack of a strong association between BTL and VTL reveals the importance of systemic vs. vascular factors in determining clinical outcomes after AMI. © The Author 2017.

Published
2017

2. ACAT1 and ACAT2 membrane topology segregates a serine residue essential for activity to opposite sides of the endoplasmic reticulum membrane.

Author

W, Joyce C, S, Shelness G, A, Davis M, G, Lee R, K, Skinner, A, Anderson R, and L, Rudel L

Abstract

A second form of the enzyme acyl-CoA:cholesterol acyltransferase, ACAT2, has been identified. To explore the hypothesis that the two ACAT enzymes have separate functions, the membrane topologies of ACAT1 and ACAT2 were examined. A glycosylation reporter and FLAG epitope tag sequence was appended to a series of ACAT cDNAs truncated after each predicted transmembrane domain. Fusion constructs were assembled into microsomal membranes, in vitro, and topologies were determined based on glycosylation site use and accessibility to exogenous protease. The accessibility of the C-terminal FLAG epitope in constructs was determined by immunofluorescence microscopy of permeabilized transfected cells. Both ACAT1 and ACAT2 span the membrane five times with their N termini in the cytosol and C termini in the ER lumen. The fourth transmembrane domain is located in a different region for each protein, placing the putative active site ACAT1 serine (Ser(269)) in the cytosol and the analogous residue in ACAT2 (Ser(249)) in the ER lumen. Mutation of these serines inactivated the ACAT enzymes. The outcome is consistent with the hypothesis that cholesterol ester formation by ACAT2 may be coupled to lipoprotein particle assembly and secretion, whereas ACAT1 may function primarily to maintain the balance of free and esterified cholesterol intracellularly.

Published
2000

4. Conjugation of hydrophobic moieties enhances potency of antisense oligonucleotides in the muscle of rodents and non-human primates.

Author

Østergaard ME, Jackson M, Low A, E Chappell A, G Lee R, Peralta RQ, Yu J, Kinberger GA, Dan A, Carty R, Tanowitz M, Anderson P, Kim TW, Fradkin L, Mullick AE, Murray S, Rigo F, Prakash TP, Bennett CF, Swayze EE, Gaus HJ, and Seth PP

Subjects
3T3-L1 Cells, Albumins metabolism, Animals, Cholesterol chemistry, Hydrophobic and Hydrophilic Interactions, Lipoproteins metabolism, Macaca fascicularis, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Oligonucleotides, Antisense metabolism, Oligonucleotides, Antisense toxicity, Palmitates chemistry, Rats, Sprague-Dawley, Tocopherols chemistry, Muscle, Skeletal, Myocardium, Oligonucleotides, Antisense chemistry
Abstract

We determined the effect of attaching palmitate, tocopherol or cholesterol to PS ASOs and their effects on plasma protein binding and on enhancing ASO potency in the muscle of rodents and monkeys. We found that cholesterol ASO conjugates showed 5-fold potency enhancement in the muscle of rodents relative to unconjugated ASOs. However, they were toxic in mice and as a result were not evaluated in the monkey. In contrast, palmitate and tocopherol-conjugated ASOs showed enhanced potency in the skeletal muscle of rodents and modest enhancements in potency in the monkey. Analysis of the plasma-protein binding profiles of the ASO-conjugates by size-exclusion chromatography revealed distinct and species-specific differences in their association with plasma proteins which likely rationalizes their behavior in animals. Overall, our data suggest that modulating binding to plasma proteins can influence ASO activity and distribution to extra-hepatic tissues in a species-dependent manner and sets the stage to identify other strategies to enhance ASO potency in muscle tissues., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Published
2019
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results