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PubMed2000

Clinical treatment of dyslipidemia: practice patterns and missed opportunities.

Studies have found that most dyslipidemic coronary artery disease and postsurgical cardiac patients are not monitored for serum lipids, especially high-density lipoprotein cholesterol (HDL-C). These patients are not prescribed lipid-altering therapy and are not treated to National Cholesterol Education Program (NCEP) target levels. When prescribed, the most commonly administered drugs are statins, followed by fibrates and niacin. Resins are the least commonly prescribed treatment for dyslipidemia. Unfortunately, drugs chosen are often not the best for each patient. To compound matters, compliance with lipid-modification therapy is poor. Nurse case-management programs, supportive regular contact with healthcare professionals, and immediate postinterventional initiation of therapy significantly improves compliance.

Age Distribution↗
PubMed2003

Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial).

The primary objective of this 6-week, parallel-group, open-label, randomized, multicenter trial was to compare rosuvastatin with atorvastatin, pravastatin, and simvastatin across dose ranges for reduction of low-density lipoprotein (LDL) cholesterol. Secondary objectives included comparing rosuvastatin with comparators for other lipid modifications and achievement of National Cholesterol Education Program Adult Treatment Panel III and Joint European Task Force LDL cholesterol goals. After a dietary lead-in period, 2,431 adults with hypercholesterolemia (LDL cholesterol > or =160 and <250 mg/dl; triglycerides <400 mg/dl) were randomized to treatment with rosuvastatin 10, 20, 40, or 80 mg; atorvastatin 10, 20, 40, or 80 mg; simvastatin 10, 20, 40, or 80 mg; or pravastatin 10, 20, or 40 mg. At 6 weeks, across-dose analyses showed that rosuvastatin 10 to 80 mg reduced LDL cholesterol by a mean of 8.2% more than atorvastatin 10 to 80 mg, 26% more than pravastatin 10 to 40 mg, and 12% to 18% more than simvastatin 10 to 80 mg (all p <0.001). Mean percent changes in high-density lipoprotein cholesterol in the rosuvastatin groups were +7.7% to +9.6% compared with +2.1% to +6.8% in all other groups. Across dose ranges, rosuvastatin reduced total cholesterol significantly more (p <0.001) than all comparators and triglycerides significantly more (p <0.001) than simvastatin and pravastatin. Adult Treatment Panel III LDL cholesterol goals were achieved by 82% to 89% of patients treated with rosuvastatin 10 to 40 mg compared with 69% to 85% of patients treated with atorvastatin 10 to 80 mg; the European LDL cholesterol goal of <3.0 mmol/L was achieved by 79% to 92% in rosuvastatin groups compared with 52% to 81% in atorvastatin groups. Drug tolerability was similar across treatments.

Adult↗
PubMed2001

A prospective study of plasma fibrinogen levels and the risk of stroke among participants in the bezafibrate infarction prevention study.

PURPOSE: Plasma fibrinogen has emerged as an important predictor of cardiovascular disease, but few data are available on its association with stroke. We sought to determine if plasma fibrinogen is a marker of increased risk or a direct causative risk factor for stroke. SUBJECTS AND METHODS: Patients from the Bezafibrate Infarction Prevention Study, a placebo-controlled, randomized clinical trial of secondary prevention of coronary heart disease by lipid modification with bezafibrate retard (400 mg daily), were studied. Plasma fibrinogen levels were measured at baseline and yearly thereafter. Stroke, a prospectively monitored endpoint, was systematically assessed regarding stroke type, subtype, and functional outcome. RESULTS: Mean baseline fibrinogen levels were significantly higher in patients subsequently having a cerebrovascular event (140 strokes, 36 transient ischemic attacks; mean follow-up, 6.2 years) than in patients who did not (375 vs. 349 mg/dL, P <0.0001). Fibrinogen levels did not differ significantly by the type, subtype, or severity of the cerebrovascular event. Risk of ischemic stroke increased from 3.3% in the lowest tertile (baseline fibrinogen <314 mg/dL) to 7.% in the middle tertile (fibrinogen 314 to 373 mg/dL) to 10% in the upper tertile (fibrinogen >373 mg/dL, P <0.001). Adjusting for age, blood pressure, and other covariates, fibrinogen levels in the upper tertile were associated with more than a twofold increase in risk of ischemic stroke compared with in the lowest tertile (hazard ratio = 2.6; 95% confidence interval: 1.5 to 4.3). We did not find fibrinogen change from baseline to be related to subsequent ischemic stroke events. CONCLUSION: Plasma fibrinogen is a strong predictor of, rather than a direct causative factor for, subsequent stroke among patients at increased risk owing to manifest coronary heart disease.

Aged↗
PubMed1997

The secondary prevention of coronary artery disease.

Randomized clinical trials demonstrate the efficacy of medical secondary prevention in coronary disease patients. The magnitude of risk reduction with exercise, diet, lipid modification, and smoking cessation is similar to other medical therapies for coronary disease such as aspirin, beta blockers, as well as coronary bypass surgery, (Table VI) In contrast to these therapies, however, secondary prevention stabilizes angiographic progression in about 50% of patients and induces regression in about 25% of patients. Both symptoms and perceived quality of life also are beneficially altered by secondary prevention programs, although possibly not by the magnitude reported for bypass surgery. These clinical trial results have led the American Heart Association, and the American College of Cardiology to strongly endorse secondary prevention. A reasonable projection based on these clinical trial data is that widespread use of these recommendations in the 12 million established coronary disease patients would significantly reduce coronary mortality and morbidity.

Coronary Disease↗
PubMed1998

Isolation and sequence of omcA, a gene encoding a decaheme outer membrane cytochrome c of Shewanella putrefaciens MR-1, and detection of omcA homologs in other strains of S. putrefaciens.

The sequence of the omcA gene, which encodes a decaheme cytochrome c that is localized to the outer membrane (OM) of Shewanella putrefaciens MR-1, was determined. The 2202 bp nucleotide sequence of omcA encodes for 734 amino acids with a predicted molecular protein mass of 78.6 kDa. Comparison with the amino-terminal sequence of the mature protein suggests the presence of a hydrophobic leader sequence which is cleaved during translocation of the protein to the OM. This leader sequence has a lipoprotein consensus sequence for signal peptidase II at the cleavage site. The predicted mature protein is comprised of 708 amino acids with a predicted molecular mass of 75.8 kDa, but the addition of ten covalently attached heme c groups and covalent lipid modification to the amino-terminal cysteine increases the predicted mass to 82.7 kDa. This is consistent with its apparent mass of 83 kDa in SDS-PAGE gels. The predicted amino acid sequence for the OmcA protein shows no significant homology to known proteins. A RNA of approx. 2300 bases that hybridizes to the omcA gene was detected in anaerobically grown MR-1 cells. The size of this transcript is similar to the coding region of the omcA gene, suggesting that it is not part of a multicistronic operon. Similar to MR-1, four other strains of S. putrefaciens were all found to localize a majority of their membrane-bound cytochromes to the OM when grown under anaerobic conditions, and all contained an OM cytochrome of similar size to OmcA. In two of these strains, MR-4 and MR-8, a homolog of omcA was identified by RT-PCR and Southern blotting using primers and probes specific for omcA of MR-1. Western blot analysis using a polyclonal antibody to OmcA was similarly positive in strains MR-4 and MR-8. Partial nucleotide sequence analysis of these homologs demonstrated 74-77% predicted amino acid homology with OmcA of MR-1. In contrast, strains MR-30 and MR-42 tested negative for omcA homologs by Southern and Northern blots, RT-PCR, and Western blots.

Amino Acid Sequence↗
PubMed1991

The NH2-terminal extension of rat liver arginyl-tRNA synthetase is responsible for its hydrophobic properties.

Rat liver arginyl-tRNA synthetase is found in extracts either as a component (Mr = 72,000) of the multienzyme aminoacyl-tRNA synthetase complex or as a low molecular weight (Mr = 60,000) free protein. The two forms are thought to be identical except for an extra peptide extension at the NH2-terminus of the larger form which is required for its association with the complex, but is unessential for catalytic activity. It has been suggested that interactions among synthetases in the multienzyme complex are mediated by hydrophobic domains on these peptide extensions of the individual proteins. To test this model we have purified to homogeneity the larger form of arginyl-tRNA synthetase and compared its hydrophobicity to that of its low molecular weight counterpart. We show that whereas the smaller protein displays no hydrophobic character, the larger protein demonstrates a high degree of hydrophobicity. No lipid modification was found on the high molecular weight protein indicating that the amino acid sequence itself is responsible for its hydrophobic properties. These findings support the proposed model for synthetase association within the multienzyme complex.

Amino Acid Sequence↗
PubMed2002

Cellular characterization of adenylate kinase and its isoform: two-photon excitation fluorescence imaging and fluorescence correlation spectroscopy.

Adenylate kinase (AK) is a ubiquitous enzyme that regulates the homeostasis of adenine nucleotides in the cell. AK1beta (long form) from murine cells shares the same protein sequence as AK1 (short form) except for the addition of 18 amino acid residues at its N-terminus. It is hypothesized that these residues serve as a signal for protein lipid modification and targeting of the protein to the plasma membrane. To better understand the cellular function of these AK isoforms, we have used several modern fluorescence techniques to characterize these two isoforms of AK enzyme. We fused cytosolic adenylate kinase (AK1) and its isoform (AK1beta) with enhanced green fluorescence protein (EGFP) and expressed the chimera proteins in HeLa cells. Using two-photon excitation scanning fluorescence imaging, we were able to directly visualize the localization of AK1-EGFP and AK1beta-EGFP in live cells. AK1beta-EGFP mainly localized on the plasma membrane, whereas AK1-EGFP distributed throughout the cell except for trace amounts in the nuclear membrane and some vesicles. We performed fluorescence correlation spectroscopy measurements and photon-counting histogram analysis in specific domains of live cells. For AK1-EGFP, we observed only one diffusion component in the cytoplasm. For AK1beta-EGFP, we observed two distinct diffusion components on the plasma membrane. One corresponded to the free diffusing protein, whereas the other represented the membrane-bound AK1beta-EGFP. The diffusion rate of AK1-EGFP was slowed by a factor of 1.8 with respect to that of EGFP, which was 50% more than what we would expect for a free diffusing AK1-EGFP. To rule out the possibility of oligomer formation, we performed photon-counting histogram analysis to direct analyze the brightness difference between AK1-EGFP and EGFP. From our analysis, we concluded that cytoplasmic AK1-EGFP is monomeric. fluorescence correlation spectroscopy proved to be a powerful technique for quantitatively studying the mobility of the target protein in live cells. This technology offers advantages in studying protein interactions and function in the cell.

Adenylate Kinase↗
PubMed2001

Functional characterization of sphingolipid C4-hydroxylase genes from Arabidopsis thaliana.

In the genome of Arabidopsis thaliana, two genes were identified encoding isoenzymes for C4-hydroxylation of long chain bases (LCB) in plant sphingolipids. Both predicted proteins consist of 258 amino acid residues (77% identity) which show sequence similarity to di-iron-binding enzymes, such as Sur2p and Erg3p from yeast, involved in oxygen-dependent lipid modifications. Heterologous expression of these genes in a yeast sur2Delta-null mutant lacking C4-LCB hydroxylation resulted in the formation of D-ribo-C(18)- and -C(20)-phytosphinganine. The identity and stereochemical configuration of the isolated trihydroxybases was confirmed by electrospray ionization-mass spectroscopy, gas-liquid chromatography-mass spectrometry and 1H-nuclear magnetic resonance spectroscopy. These results represent the first functional identification of SUR2 genes from plants as well as from any organism other than yeast.

Arabidopsis↗
PubMed2001

Identification and characterisation of Toxoplasma gondii protein farnesyltransferase.

Prenylated proteins are involved in the regulation of DNA replication and cell cycling and have important roles in the regulation of cell proliferation. Protein farnesyltransferase and protein geranylgeranyltransferase are the two enzymes responsible for catalysing isoprene lipid modifications. Recently these enzymes have been targets for the development of cancer chemotherapeutics. Using metabolic labelling we identified isoprenylated proteins which suggests the presence of protein farnesyltransferase in Toxoplasma gondii. T. gondii protein farnesyltransferase is heat-labile and requires Mg(2+) and Zn(2+) ions for full activity. Peptidomimetic analogues as well as short synthetic peptides were tested in vitro as possible competitors for farnesyltransferase substrates. We found that the synthetic peptide (KTSCVIA) specifically inhibited T. gondiiprotein farnesyltransferase but not mammalian (HeLa cells) farnesyltransferase. Therefore this study suggests the possible development of specific inhibitors of T. gondiiprotein farnesyltransferase as an approach to parasitic protozoa therapy.

Alkyl and Aryl Transferases↗
PubMed2003

Lymphocytes apoptosis: young versus aged and humans versus rats.

This paper deals with a comparative study of lymphocyte apoptosis in young versus aged and humans versus rats. Apoptotic rate achieved by the use of different apoptogenic inducers, acting at different cellular levels, and cell surface modifications were analyzed. The results showed that aged human lymphocytes and freshly isolated rat lymphocytes were more prone to undergo apoptosis. Therefore, the same apoptotic signal is recognized by human and rat lymphocytes, but the extent of the answer is related to the species, to the intensity of the apoptotic stimulus and to the metabolic/developmental condition of the cells. Surface modifications (lipids and glycans), typical of apoptosis, were observed. Our data showed that cell surface changes are species and age dependent. They are early events, progressively achieved in the course of the apoptotic process involving lateral membrane movements of molecules.

Adult↗
PubMed2005

Purification and properties of Rab3 GEP (DENN/MADD).

Rab3A, a member of the Rab3 small GTP-binding protein (G protein) family, regulates Ca(2+)-dependent exocytosis of neurotransmitter. Rab3A cycles between the GDP-bound inactive and GTP-bound active forms, and the former is converted to the latter by the action of a GDP/GTP exchange protein (GEP). We have previously purified a GEP from rat brain with lipid-modified Rab3A as a substrate. Purified Rab3 GEP is active on all the Rab3 subfamily members including Rab3A, -3B, -3C, and -3D. Purified Rab3 GEP is active on the lipid-modified form, but not on the lipid-unmodified form. Purified Rab3 GEP is inactive on Rab3A complexed with Rab GDI. The recombinant protein is prepared from the Rab3 GEP-expressed Spodoptera frugiperda cells (Sf9 cells). The properties of recombinant Rab3 GEP, including the requirement for lipid modifications of Rab3A, the substrate specificity, and the sensitivity to Rab GDI, are similar to those of purified Rab3 GEP. Overexpression of Rab3 GEP inhibits Ca(2+)-dependent exocytosis from PC12 cells. On the other hand, Rab3 GEP is identical to a protein named DENN/MADD: differentially expressed in normal versus neoplastic (DENN)/mitogen-activated protein kinase-activating death domain (MADD). Here, we describe the purification method for recombinant Rab3 GEP from Sf9 cells and the functional properties of Rab3 GEP in Ca(2+)-dependent exocytosis by use of the human growth hormone coexpression assay system of PC12 cells.

Animals↗
PubMed2006

A tagging-via-substrate technology for genome-wide detection and identification of farnesylated proteins.

Protein farnesylation is one of the most common lipid modifications and has an important role in the regulation of various cellular functions. We have recently developed a novel proteomics strategy, designated the tagging-via-substrate (TAS) approach, for the detection and proteomic analysis of farnesylated proteins. This chapter describes the principle of TAS technology and details the method for detection and enrichment of farnesylated proteins.

Animals↗
PubMed2006

Biochemical analyses of the Wrch atypical Rho family GTPases.

The Rho family of GTPases comprises a major branch of the Ras superfamily of small GTPases. To date, at least 22 human members have been identified. However, most of our knowledge of Rho GTPase function comes from the study of the three classical Rho GTPases, RhoA, Rac1, and Cdc42. These Rho GTPases function as GDP/GTP-related binary switches that are activated by diverse extracellular signal-mediated stimuli. The activated GTPases then interact with downstream effectors to regulate cytoplasmic signaling networks that in turn regulate actin organization, cell cycle progression, and gene expression. Recently, studies have begun to explore the regulation and function of some of the lesser-known members of the Rho GTPase family. Wrch-1 (Wnt-regulated Cdc42 homolog-1) and the closely related Chp (Cdc42 homologous protein)/Wrch-2 protein comprise a distinct branch of the mammalian Rho GTPase family. Although both share significant sequence and functional similarities with Cdc42, Wrch proteins possess additional N- and C-terminal sequences that distinguish them from the classical Rho GTPases (Cdc42, RhoA, and Rac1). We have determined that Wrch-1 and Wrch2 exhibit unusual GDP/GTP binding properties and undergo posttranslational lipid modifications distinct from those of the classical Rho GTPases. In this chapter, we summarize our experimental approaches used to characterize the biochemical properties of these atypical Rho GTPases.

Animals↗
PubMed2001

Structural determinants of fast inactivation of high voltage-activated Ca(2+) channels.

The fast inactivation of voltage-dependent Ca(2+) channels is a key mechanism that contributes to the precise control of Ca(2+) entry into excitable cells. Recent advances have revealed that multiple structural elements contribute to the intrinsic inactivation properties of the alpha(1) subunit, including its cytoplasmic and transmembrane regions. Another major determinant of Ca(2+) channel inactivation is the association with one of four types of ancillary beta subunits that differentially modulate the intrinsic inactivation properties of the alpha(1) subunit. This could occur partly via interactions with the N-terminal region of the alpha(1) subunit and through lipid modification of the beta subunit. However, the latest findings suggest a mechanism in which fast Ca(2+) channel inactivation could occur through physical occlusion of the pore of the channel in a manner reminiscent of Na(+) and K(+) channel inactivation.

Animals↗
PubMed2002

Inhibition of Rho/Rho-kinase signaling downregulates plasminogen activator inhibitor-1 synthesis in cultured human monocytes.

Increased production of plasminogen activator inhibitor-1 (PAI-1) in plaques plays a role in the pathogenesis of atherosclerosis. This study was conducted to investigate the effect of blockade of Rho/Rho-kinase signaling on the synthesis of PAI-1 in cultured human peripheral blood monocytes. HMG-CoA reductase inhibitors (statins) and inhibitors of Rho and Rho-kinase were added to monocyte cultures. The levels of PAI antigen and mRNA were determined by Western blotting and RT-PCR, respectively, and PAI-1 expression was assessed by immunohistochemistry. We performed pull-down assays to determine the activity of Rho by measuring the GTP-bound form of Rho A. In unstimulated and lipopolysaccharide (LPS)-stimulated cultured monocytes, statins reduced the levels of PAI-1 antigen and mRNA. The suppressive effects of statins on PAI-1 synthesis were reversed by geranylgeranylpyrophosphate (GGPP) and were mimicked by C3 exoenzyme. Immunohistochemistry confirmed the role of lipid modification by GGPP in suppressive effect of statins in PAI-1 synthesis. Pull-down assays demonstrated that statins decreased the levels of the GTP-bound form of Rho A. Our findings suggest that statins decrease the activity of Rho by inhibiting geranylgeranylation. Moreover, Rho-kinase inhibitors, Y-27632 and fasudil, suppressed the synthesis of PAI-1 in this culture system. We show that inhibition of Rho/Rho-kinase signaling downregulates the synthesis of PAI-1 in human monocytes.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2001

Estrogen/progesterone replacement versus pravastatin and their sequential association in hypercholesterolemic postmenopausal women.

OBJECTIVES: The objectives of this study were to assess serum lipid changes in response to an oral estrogen combined with progesterone (Group A) as compared with pravastatin (Group B) and to evaluate the additive effects of the sequential addition of statin to hormonal replacement therapy (HRT) and of HRT to statin. METHODS: Thirty-seven of 63 hypercholesterolemic menopausal women initially submitted to a 4-month diet were randomised to oral conjugated estrogens (0.625 mg)/micronised progesterone (200 mg) or to pravastatin (40 mg). After 6 months, each group received both medications for another 6 months. RESULTS: Nineteen percent of women corrected their lipids below decision levels with diet alone. Low density lipoprotein-cholesterol (LDL-C) decreased by 8+/-5% with HRT and by 26+/-3% (P<0.001) with the statin. These single medications increased high density lipoprotein-cholesterol (HDL-C) by 13+/-5% (P<0.01) and 11+/-7%, respectively. Combined interventions produced cumulative LDL-C reductions of 40+/-2 and 42+/-3% (P<0.001) and additive HDL-C augmentations of 16+/-4 and 23+/-5% (P<0.01) with proportional changes in apolipoprotein (Apo)B-100 and ApoA-1. These combined effects brought the atherogenic index (C/HDL-C) for Groups A and B, respectively, from a moderate (5.18+/-0.25 and 5.87+/-0.18) to a reduced (3.35+/-0.20 and 3.52+/-0.19) risk category. Triglycerides (TG) which were increased by HRT and decreased by the statin returned to baseline during combined treatments. No changes in diet, physical activity or anthropomorphometric measurements explained the lipid modifications. CONCLUSIONS: In menopausal patients with elevated C not responding to diet, pravastatin was most effective to decrease LDL-C, and oral estrogen-micronised progesterone most effective to increase HDL-C. Marked reduction of the atherogenic index is achieved by sequential combinations of medications resulting from beneficial cumulative effects on both C-LDL and C-HDL.

Administration, Oral↗
PubMedDate not supplied

Sonic Hedgehog signalling in the developing and adult brain.

Sonic Hedgehog (Shh) belongs to a family of secreted polypeptides implicated in embryonic development. Shh displays inductive, proliferative, neurotrophic and neuroprotective activities on various neural cells and signals through a receptor complex associating Patched (Ptc) and Smoothened (Smo). Shh binding to Ptc leads to downstream activation of target genes, such as transcription factors of the Gli family. We have investigated the distribution of Shh signalling genes in the rat embryo and in the adult, as well as pharmacological properties of Shh peptides. In the ventral neural tube, the distribution of Shh, Ptc and Smo is in agreement with this functional model. In the postnatal cerebellum, Shh expressed by Purkinje cells may act on its target receptor complex localized in the external germinative layer to activate Gli1. Myristoylated ShhN (myrShhN) is more potent than ShhN in stimulating proliferation of rat cerebellar granule cell neuroblasts in culture, as evaluated by [3H]thymidine incorporation, suggesting that amino terminal lipid modification of the molecule plays a crucial role in ShhN biological activity. In the adult brain, Ptc and Smo transcripts are colocalized in a few areas such as the hippocampal granule cells. However, Ptc transcripts are also observed without any detectable Smo expression, such as in the superior colliculus. These observations suggest that in the adult brain, Shh signals through its receptor complex Ptc/Smo, or through Ptc alone. Ptc protein presents a sterol sensing domain which has been identified in several proteins, including TRC8, recently implicated in hereditary renal carcinoma and which is also expressed as a 2.5-kb transcript in several rat brain areas. Altogether, these results suggest other roles for Shh signalling in postnatal and adult brain than those initially established during early embryonic development.

Aging↗
PubMed2002

Molecular machinery required for autophagy and the cytoplasm to vacuole targeting (Cvt) pathway in S. cerevisiae.

Autophagy is a vacuolar trafficking pathway that targets subcellular constituents to the vacuole for degradation and recycling. In nutrient-rich conditions in yeast, a different vacuolar trafficking pathway, the cytoplasm to vacuole targeting (Cvt) pathway, transports the resident hydrolase aminopeptidase I to the vacuole, using many of the same molecular components as autophagy. The Cvt pathway is constitutive, whereas autophagy is induced by starvation. Recent studies have laid important groundwork for understanding the signaling mechanism that induces autophagy. Another key advance has been the identification of two novel conjugation systems that function in vesicle formation in both pathways. Finally, many autophagy- and Cvt-specific gene products, including those involved in lipid modification, vesicle expansion and cargo specificity, have been shown to localize to a novel perivacuolar membrane compartment. Additional analysis of this location will help in further dissecting the early events of vesicle formation and identifying the source of the sequestering membrane.

Autophagy↗