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PubMed2003

Sp and GATA factors are critical for Apolipoprotein AI downstream enhancer activity in human HepG2 cells.

The factors that bind to the hepatic-specific human apolipoprotein AI (apoAI) 48-bp downstream enhancer (DSE) were identified and characterized by electrophoretic mobility shift assays. A significant homology was shown between the histone 4 (H4) promoters and the hepatic-specific human apoAI DSE at Sp1 and H4TF2 binding sites. Human HepG2 nuclear extracts were used to form four specific complexes with the DSE (referred to as apoAI DSE-1, -2, -3, and -4). The apoAI DSE-1 and -2 complexes showed similar binding specificity to the Sp/H4TF1 consensus site within the apoAI DSE. The apoAI DSE-1 complex was predominantly recognized by anti-Sp1 and Sp3 sera in gel shift assays, indicating that the DSE was recognized by multiple Sp family members. Nuclear extracts that were prepared from retinoic acid treated HepG2 cells showed increased levels of Sp factors in gel shift and Western blot assays. The apoAI DSE-2 complex was identified as H4TF1 and formed in the absence of magnesium chloride. The apoAI DSE-3 complex bound to a consensus GATA element within the DSE that was recognized by recombinant human GATA-6 as well. The apoAI DSE-3 complex was completely disrupted by a GATA-4 antibody in EMSA. GATA-4 and -6 were detected in nuclear extracts prepared from retinoic acid treated HepG2 cells using Western blot assays. The highest apoAI DSE-3 levels were observed with retinoic acid treated HepG2 cell nuclear extracts in EMSA. ApoAI DSE-4 is a multi-factor complex that includes an Sp/H4TF1 factor and either H4TF2 or apoAI DSE-3. Because apoAI DSE mutations revealed transcription defects in transient transfection assays, we conclude that the entire DSE sequence is required for full apoAI transcriptional activity in HepG2 cells.

Apolipoprotein A-I↗
PubMed2026

Intervention Without Borders - an Automated Self-Guided AI-Enhanced Psychoeducation Intervention for Dementia Caregivers: Parallel-Group Randomized Waitlist-Controlled Trial.

OBJECTIVE: To examine whether a fully automated, self-guided intervention (PDC30) could improve caregiver well-being over a 1-month waitlist control in an international sample. DESIGN: Randomized waitlist-controlled trial. SETTING: Web-based platform accessible globally. PARTICIPANTS: 441 individuals responded to study promotion on the internet, of whom 274 from 43 countries met the study criteria and were randomized. Eligible participants were adults providing ≥10 care hours weekly to community-dwelling relatives with dementia, scoring ≥5 on Patient Health Questionnaire-9 (PHQ-9), and without recent caregiver intervention. INTERVENTION: Available 24/7, PDC30 is a self-guided, automated intervention consisting of a Guidebook, an AI-powered counseling chatbot, and interactive applications for cognitive-behavioral techniques, relaxation, and caregiver-recipient bonding. MEASUREMENTS: At baseline and follow-ups at 1, 2, and 3 months, depression was assessed by PHQ-9. Secondary outcomes were measured with validated brief versions of anxiety, burden, and positive gains. RESULTS: Intent-to-treat analysis using mixed-effects regression showed treatment x time2 effects on all outcomes except anxiety. At 1-month follow-up, coinciding with exclusive access to PDC30, intervention caregivers showed significant improvements in depression (d = -0.37), burden (d = -0.34), and positive gains (d = 0.42). The differences mostly disappeared after control participants received the intervention, while improvements in both groups were sustained thereafter. Participants reported using the website several times weekly, were generally satisfied with it, and found the chatbot most helpful. CONCLUSIONS: The effects on depression and other outcomes were consistent with those observed for in-person programs, suggesting the viability of well-designed automated intervention. The study demonstrates the feasibility, acceptability, and potential global health impact of PDC30.

Humans↗
PubMed2004

Associations between serum high-density lipoprotein cholesterol or apolipoprotein AI levels and common genetic variants of the ABCA1 gene in Japanese school-aged children.

ATP-binding cassette transporter A1 (ABCA1) plays an important role in apolipoprotein AI (apoAI)-mediated cholesterol efflux from peripheral cells. The mild changes in ABCA1 activity due to genomic variation might be associated with interindividual variations in serum high-density lipoprotein cholesterol (HDL-C) and apoAI levels, or primary hypoalphalipoproteinemia in the general population. In the present study, we analyzed the relationships between 5 single nucleotide polymorphisms (SNPs) and 2 insertion/deletion polymorphisms in the 5' flanking region and 5 missense polymorphisms of the ABCA1 gene and serum lipid levels in healthy school-aged children. We detected significant associations between the K219R and V771M polymorphisms, and HDL-C or apoAI levels. The present data support the proposition that the K219 allele is an anti-atherogenic allele with increased cholesterol efflux activity. Similarly, the M771 allele appears to be anti-atherogenic, although the frequency of the M771 allele is low.

5' Flanking Region↗
PubMed2004

Effect of glucosamine on apolipoprotein AI mRNA stabilization and expression in HepG2 cells.

Previously published studies suggest that an alteration in hexosamine flux induces a state of insulin resistance in muscle, liver, and other cell types. Glucosamine also alters the expression of several genes through an effect on transcription factors such as Sp1. Since the anti-atherogenic protein apolipoprotein AI (apoAI) is positively regulated by insulin, at least partly through its effect on Sp1, we investigated the effect of glucosamine on apoAI gene expression in the hepatocyte cell line, HepG2. By 24 hours of treatment with 0.1, 1, or 3 mmol/L glucosamine, the amount of apoAI protein secreted into the culture media increased 1.8-fold, 5.5-fold, and 2.3-fold, respectively. The decline in apoAI secretion at the highest glucosamine levels may be due to toxicity since the percentage of cells able to exclude trypan blue was lower in this group than in control cells (98.5% +/- 1.5% in control cells v 89.2% +/- 2.1% in cells treated with 3 mmol/L glucosamine, P <.01). ApoAI mRNA levels increased 2.4-fold in hepatocytes treated with 1 mmol/L glucosamine for 24 hours (1,158.1 +/- 78.8 v 482.2 +/- 24.3 arbitrary integrator units [AIU], P <.02), suggesting that the increase in apoAI protein secretion was due, at least partly, to an increase in apoAI mRNA levels. However, glucosamine had no effect on apoAI gene transcription rate as measured by nuclear runoff analysis (3,155 +/- 46.0 in control cells v 3,181 +/- 30.0 AIU in glucosamine-treated cells). Similarly, apoAI promoter activity measured in HepG2 cell transfected with an apoAI reporter plasmid containing the full-length apoAI promoter including an insulin-responsive Sp1 binding site did not change with glucosamine addition. In this assay, the chloramphenicol acetyltransferase (CAT) activity was 12.4% +/- 3.1%, 10.1% +/- 2.4%, 9.8% +/- 2.0%, 9.7% +/- 2.2%, and 11.9% +/- 2.9% in cells treated with 0, 0.03, 0.1, 0.3, and 1 mmol/L glucosamine, respectively. The apoAI mRNA turnover studies showed that 1 mmol/L glucosamine treatment of HepG2 cells was associated with increased apoAI mRNA half-life, from 7.6 to 16.6 hours. These findings suggest that increases in apoAI gene expression by glucosamine occur primarily through stabilizing apoAI mRNA.

Apolipoprotein A-I↗
PubMed2004

Phosphatidylinositol 3-kinase, phosphoinositide-specific phospholipase-Cgamma and protein kinase-C signal myelin phagocytosis mediated by complement receptor-3 alone and combined with scavenger receptor-AI/II in macrophages.

Complement-receptor-3 (CR3/MAC-1), scavenger-receptor-AI/II (SRAI/II) and Fcgamma-receptor (FcgammaR) can mediate phagocytosis of degenerated myelin in macrophages and microglia. However, CR3/MAC-1 and SRAI/II, but not FcgammaR, mediate phagocytosis after axonal injury. We tested for phosphatidylinositol 3-kinase (PI3K), phosphoinositide-specific phospholipase-Cgamma (PLCgamma) and protein kinase-C (PKC) signaling in myelin phagocytosis mediated by CR3/MAC-1 alone and by CR3/MAC-1 combined with SRAI/II. Phagocytosis was inhibited by PI3K inhibitors wortmannin and LY-294002, PLCgamma inhibitor U-73122, classical PKC (cPKC) inhibitor Go-6976, general PKC inhibitors Ro-318220 and calphostin-C, and BAPTA/AM which chelates intracellular Ca(2+) required for cPKC activation. PKC activator PMA augmented phagocytosis and further alleviated inhibitions induced by PI3K and PLCgamma inhibitors. Overall, altering PKC activity modulated phagocytosis 4- to 6-fold between inhibition and augmentation. PLCgamma activation did not require tyrosine phosphorylation. Thus, signaling of myelin phagocytosis mediated by CR3/MAC-1 alone and by CR3/MAC-1 combined with SRAI/II involves PI3K, PLCgamma and cPKC, the cascade PI3K-->PLCgamma-->cPKC, and wide-range modulation by PKC. This pathway may thus be targeted for in vivo modulation, which may explain differences in the efficiency of CR3/MAC-1-mediated myelin phagocytosis in different pathological conditions.

Animals↗
PubMed2005

High yield and secretion of recombinant human apolipoprotein AI in Pichia pastoris.

Apolipoprotein AI (ApoAI) is an important apolipoprotein in plasma and is known to have various physiological functions suitable for pharmaceutical applications. Human blood has been the only source of this protein for research and large-scale applications. To obtain large amounts of ApoAI a Pichia pastoris expression system was first used to obtain a high level of expression of secreted, recombinant protein. The human gene encoding ApoAI was inserted into the secretion vector pPIC9K and used to transform P. pastoris GS115. AP16, a high expression transformant with high G418 resistance, was obtained. After induction with methanol, the expression level of rhApoAI (recombinant human ApoAI) was 160 mg/L in a 14L fermentor. RhApoAI was purified by cold acetone precipitation followed by Q-Sepharose Fast Flow ion exchange column chromatography with 60% recovery. The N-terminal amino acid sequence and molecular weight (mass spec.) of rhApoAI are identical to native human ApoAI. Purified rhApoAI has specific binding activity with liver cells SMC7721 and binding can be inhibited by native human ApoAI.

Apolipoprotein A-I↗
PubMed2005

Sperm chromatin stability in frozen-thawed semen is maintained over age in AI bulls.

The aim of the present study was to investigate the effect of age of the sire on the in vitro quality of frozen-thawed (FT) bull spermatozoa, both when tested immediately postthaw (PT) and when assessed after cleansing and selection through a swim-up (SU) procedure. Semen samples from six Swedish Red and White Breed (SRB) artificial insemination (AI) bulls at age 1 and again, at 4 years were collected and frozen in 0.25 ml plastic straws. Also, semen was collected from six Estonian Holstein (EHF) bulls at the ages of 3, 5, and 7 years and likewise processed. The FT semen was tested for the susceptibility of sperm nuclear deoxyribonucleic acid (DNA) to undergo acid-induced denaturation in situ, as quantified by flow cytometry (FCM). The DNA denaturability was expressed as function alpha t, i.e., as the ratio of red (denaturated DNA) to red + green (total cellular DNA) fluorescence intensity. The results were expressed as the percentage of cells with high alpha t values, i.e., cells outside the main population (% COMP alpha t). Morphological evaluation of the same samples was performed to detect general and sperm head abnormalities and differences between ages. Fertility results were available as non-return rates (NRRs) for the semen of the sires when they were 1 year (SRB) and 3 years (EHF) old, varying from 62.2 to 70.7% in SRB and from 52.2 to 76.0% in EHF animals. The COMP alpha t values ranged from 0.5-3.6% (PT) to 0.2-1.7% (SU) for SRB bulls and from 0.4-1.8% (PT) to 0.2-1.5% (SU) for EHF bulls. Both breeds lacked differences between ages, either PT or after SU. However, the SU procedure yielded a significantly higher population of spermatozoa with stable DNA following acid-induced denaturation, than PT samples (p < 0.001). No correlation was detected between field fertility and chromatin stability. The results indicate that for these bull populations, the SU procedure was able to select spermatozoa with stable chromatin from the bulk samples. However, the use of DNA denaturation as a challenge to assess sperm chromatin stability did not offer a more accurate tool to evaluate sperm quality than the conventional, light microscopical evaluation of morphology.

Aging↗
PubMed2005

Progesterone (CIDR)-based timed AI protocols using GnRH, porcine LH or estradiol cypionate for dairy heifers: ovarian and endocrine responses and pregnancy rates.

The overall objective was to compare the efficacy of GnRH, porcine LH (pLH) and estradiol cypionate (ECP), in a modified Ovsynch/fixed-time AI (FTAI) protocol that included a controlled internal drug [progesterone] release (CIDR) device. In Experiment 1, heifers received a CIDR on Day -10, and PGF (25mg) on Day -3. At CIDR insertion, heifers received 100 microg of GnRH (n=6), 0.5mg of ECP (n=6), 5.0mg of pLH (n=6) or 2 mL of saline (n=7); these treatments were repeated on Day -1, except for ECP, that was repeated on Day -2, concurrent with CIDR-removal. The 5.0 mg pLH was the least effective with a longer interval to ovulation than the other groups combined (102 versus 64 h; P<0.05). Overall mean LH concentrations (1.6 ng/mL) and area under the curve (AUC) did not differ among treatments, but mean peak LH concentration was lower in heifers given 5 mg of pLH compared to all other groups (4.5 versus 10.3 ng/mL; P<0.05). In Experiment 2, heifers on CIDR-based Ovsynch protocols were given 12.5mg pLH (n=6; pLH-low), 25.0 mg pLH (n=6, pLH-high), or 100 microg GnRH (n=5; control). Heifers in the pLH-high group had greater (P<0.01) plasma LH concentrations (between 12 and 20 h) than GnRH-treated heifers, but the pLH treatments did not differ (P>0.10). Area under the curve for LH (ng/32 h) was at least 50% greater (P<0.01) in pLH-treated heifers compared to GnRH-treated heifers (mean, 41.3, 56.3 and 20.3 for pLH-low, pLH-high and GnRH, respectively). Ovulation occurred in 15 of 17 heifers. Progesterone concentrations were higher on Days 9 and 14 in heifers given 25mg of pLH, suggesting enhanced CL function. In Experiment 3, 240 heifers were assigned to CIDR-based Ovsynch/FTAI protocols. The first and second hormonal treatments (with an intervening PGF treatment on Day -3) were GnRH/GnRH (100 microg), ECP/ECP (0.5 mg), pLH/pLH (12.5 mg) or GnRH/ECP, respectively; pregnancy rates were 58.7, 66.1, 45.9 and 48.3%, respectively (ECP/ECP>both pLH/pLH and GnRH/ECP; P<or=0.05). In conclusion, CIDR-based Ovsynch/FTAI protocols using either GnRH/GnRH or ECP/ECP yielded pregnancy rates about 20% points higher than previously reported for dairy heifers bred to Ovsynch/FTAI in the absence of a CIDR.

Administration, Intravaginal↗
PubMed2025

In silico generation of synthetic cancer genomes using generative AI.

Understanding how genomic alterations drive cancer is key to advancing precision oncology. To detect these alterations, accurate algorithms are used; however, due to privacy concerns, few deeply sequenced cancer genomes can be shared, limiting benchmarking and representing a major obstacle to the improvement of analytic tools. To address this, we developed OncoGAN, a generative AI model combining adversarial networks and variational autoencoders to create realistic synthetic cancer genomes. Trained on large-scale genomic datasets, OncoGAN accurately reproduces somatic mutations, copy number alterations, and structural variants across cancer types while preserving donors' privacy. The synthetic genomes reflect tumor-specific mutational signatures and positional mutation patterns. Using DeepTumour, we validated the synthetic data's fidelity, showing high concordance between generated and predicted tumors. Moreover, augmenting the training data with synthetic genomes improved DeepTumour's accuracy, underscoring OncoGAN's potential to generate shareable datasets with known ground truths for benchmarking and enhancement of cancer genome analysis tools.

Humans↗
PubMed2000

Apolipoprotein AI and transthyretin as components of amyloid fibrils in a kindred with apoAI Leu178His amyloidosis.

We found a new C-terminal amyloidogenic variant of apolipoprotein AI (apoAI), Leu178His in a French kindred, associated with cardiac and larynx amyloidosis and skin lesions with onset during the fourth decade. This single-point mutation in exon 4 of the apoAI gene was detected by DNA sequencing of polymerase chain reaction amplified material and restriction fragment length polymorphism analysis in two siblings. Blood, larynx, and skin biopsies were available from one sibling. Anti-apoAI immunoblotting of isoelectric focusing of plasma showed a +1 alteration in the charge of the protein. Extraction of fibrils from the skin biopsy revealed both full-length and N-terminal fragments of apoAI and transthyretin (TTR). ApoAI and TTR co-localized in amyloid deposits as demonstrated by immunohistochemistry. The present report, together with the first recently described C-terminal amyloidogenic variant of apoAI, Arg173Pro, shows that amyloidogenicity of apoAI is not a feature exclusive to N-terminal variants. The most striking characteristic of amyloid fibrils in Leu178His is that wild-type TTR is co-localized with apoAI in the fibrils. We have previously determined that a fraction of plasma TTR circulates in plasma bound to high-density lipoprotein and that this interaction occurs through binding to apoAI. Therefore we hypothesize that nonmutated TTR might influence deposition of apoAI as amyloid.

Adult↗
PubMed1998

Conformation of apolipoprotein AI in reconstituted lipoprotein particles and particle-membrane interaction: effect of cholesterol.

Discoidal recombinant high density lipoproteins (rHDL) of apolipoprotein AI (apoAI) and palmitoyloleoylphosphatidylcholine (POPC), with or without cholesterol, were prepared by cholate dialysis. By gel filtration, rHDL containing 2-4 (Lp2, Lp3 and Lp4) apoAI molecules/particle were obtained. The ApoAI conformation in these rHDL was investigated by tryptophan fluorescence, denaturation with guanidine HCl, and immunoreactivity with two monoclonal antibodies recognizing epitopes in the N-terminal and central domains. Data show that apoAI conformation is highly dependent on particle size as well as on cholesterol. The ability of rHDL to interact with lipid bilayer was studied by measuring leakage induction on POPC and POPC/cholesterol vesicles loaded with terbium/dipicolinic acid. Among the cholesterol-free rHDL, the most efficient ones were the smallest Lp2. Leakage induction on POPC vesicles is dramatically decreased by the presence of cholesterol in Lp2 and Lp3. All the rHDL, but specially those containing cholesterol, induced more leakage on the POPC/cholesterol than on the POPC vesicles. These results suggest that in small cholesterol-poor particles, apoAI could have a conformation determining a high affinity for membranes, which could facilitate cholesterol efflux. After cholesterol enrichment, a conformational change in apoAI could decrease the affinity for membranes allowing the lipoprotein release.

Antibodies, Monoclonal↗
PubMed1988

Variant apolipoprotein AI as a major constituent of a human hereditary amyloid.

Amyloid fibrils were isolated from spleen and liver of a patient who died with Familial Amyloidotic Polyneuropathy Type III (Iowa). The major protein constituent of the fibrils was found to be the amino terminal portion (residues 1-83) of apolipoprotein AI with an arginine for glycine substitution at position 26. This is the first report of an apolipoprotein as a major amyloid constituent in a form of autosomal dominant hereditary amyloidosis in humans.

Amino Acid Sequence↗
PubMed2003

Plaque-associated endothelial dysfunction in apolipoprotein E-deficient mice on a regular diet. Effect of human apolipoprotein AI.

OBJECTIVE: Apolipoprotein E-deficient mice (apoE(-/-)) on a regular diet become hypercholesterolemic and develop atherosclerosis, but endothelium-dependent relaxation remains undisturbed for up to 6 months. We investigated whether vasomotor dysfunction develops in aged apoE(-/-), whether the defect was systemic (hypercholesterolemia-dependent) or focal (plaque-related), and the effect of human apolipoprotein AI transgenesis (apoAI/E(-/-)). METHODS: Arteries of apoE(-/-) (n=5), apoAI/E(-/-) (n=6) and C57Bl/6J (WT, n=4) mice (18 months) were systematically dissected for isometric tension recording and subsequent morphometry. RESULTS: Acetylcholine (ACh)-induced relaxation was impaired (P<0.01) in atherosclerotic segments of apoE(-/-) (26+/-14%) as compared to WT mice (93+/-2%). Similar reduced (P<0.01) responses to adenosine 5'-triphosphate (apoE(-/-) 38+/-14, WT 94+/-3%) and the calcium ionophore A23187 (apoE(-/-) 19+/-6%, WT 97+/-2%) pointed to a post-receptor defect. Indeed, responses to exogenous nitric oxide were impaired in atherosclerotic segments as well (apoE(-/-) 71+/-7%, WT 92+/-1%, P<0.05). Furthermore, relaxations inversely correlated with plaque size (ACh r(s)=-0.74, P<0.01). In adjacent plaque-free segments however, responses to ACh (apoE(-/-) 92+/-3%, WT 97+/-1%) and all other agents were preserved, despite the prolonged hypercholesterolemia. ApoAI improved vasomotor responses in atherosclerotic segments. However, negative correlations between maximal relaxation and plaque area remained in apoAI/E(-/-) mice (ACh r(s)=-0.67, P<0.01). Indeed, covariate analysis of variance did not point to direct protection of vasomotor function by apoAI when the smaller lesions were taken into account. CONCLUSIONS: Endothelial dysfunction in apoE(-/-) mice is not affected by hypercholesterolemia alone, but is strictly associated with plaque formation. Human apoAI transgenesis-known to raise HDL-attenuated atherogenesis, thereby indirectly improving relaxation responses in apoE(-/-) mice.

Animals↗
PubMed2000

Absence of relationship between plasma Lp(a), Lp-AI, anti-oxidized LDL autoantibodies, LDL immune complexes concentrations and restenosis after percutaneous transluminal coronary angioplasty.

To determine the relation between the concentration of Lp(a), LpAI, immunological markers of LDL oxidation (antioxidized-LDL autoantibodies (LDL-AB), LDL immune complexes (LDL-IC)) and restenosis after percutaneous transluminal coronary angioplasty (PTCA) in a Caucasian population (France), we studied 77 consecutive patients who successfully underwent PTCA. All were evaluated by follow-up angiography at an average of 6 months after PTCA and were divided into two groups: existence of restenosis (32 patients, group (G+)) and absence of restenosis (45 patients, negative group (G-)). The prevalence of diabetes mellitus was higher in the restenosis positive group than in the negative group (28% versus 2% respectively, P=0.001). Before and after adjustment in diabetes mellitus frequency there was no difference in the usual lipid parameters (total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, phospholipids, apolipoprotein AI, apolipoprotein B) between the two groups of patients nor in the other parameters (Before adjustment: Lp(a): 0.306+/-0.352 g/l (G+) vs. 0.263+/-0.270 g/l (G-); LpAI: 0.414+/-0.126 g/l (G+) vs. 0.390+/-0.092 g/l (G-); LDL-AB: arbitrary unit (AU) 3.75+/-1.91 (G+) vs. 3.67+/-1.24 (G-); LDL-IC: (AU) 0.93+/-0.82 (G+) vs. 0.86+/-0.44 (G-)). Spearman correlation coefficients did not report any correlation between late loss, loss index, gain and the above mentioned plasma parameters. In conclusion, usual tested plasma lipids, Lp(a), LpAI and in vivo markers of LDL oxidation (LDL-AB and LDL-IC) are not risk factors for restenosis after PTCA in this French population.

Aged↗
PubMed2001

Coronary artery disease in patients at low risk--apolipoprotein AI as an independent risk factor.

Many risk factors for coronary artery disease (CAD) have been established by large epidemiological studies. However, some patients without the major risk factors still develop disease. Preliminary analysis of individuals referred for angiography, who had no major risk factors associated with CAD, indicated that apolipoprotein-AI (apoAI) was significantly lower in patients with positive angiograms. The hypothesis that apoAI was an independent risk factor for CAD in low risk populations was put forth. One thousand and seventy-five consecutive patients underwent angiography, lipid analysis, and completed a risk factor questionnaire. Individuals with total cholesterol<5.2 mmol/l, high density lipoprotein (HDL)-cholesterol>0.9 mmol/l, systolic blood pressure<140 mmHg and diastolic blood pressure<90 mmHg, no diabetes, and no family history of premature CAD in first degree relatives were selected. Fifty-four patients met these selection criteria, 29 having positive evidence of CAD and 25 with no evidence of disease. Multivariate analysis revealed that, after adjusting for age and gender, serum apoAI level was the only variable predictive of CAD. This effect was independent of HDL cholesterol level and fractional esterification rate of HDL (FER(HDL)). These results point to an important role for apoAI in the atherogenic process, particularly in populations with no major CAD risk factors. Decreased levels of apoAI or LpAI may initiate atherosclerosis in a highly selected group of low risk patients.

Apolipoprotein A-I↗
PubMed2002

Simvastatin, an HMG-CoA reductase inhibitor, induces the synthesis and secretion of apolipoprotein AI in HepG2 cells and primary hamster hepatocytes.

Clinical studies have recently suggested that statin treatment may beneficially elevate plasma concentrations of high density lipoprotein (HDL)-cholesterol in patients with hyperlipidemia. Here, we have investigated the effect of a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase on the synthesis and secretion of apolipoprotein AI (apoAI) in two model systems, HepG2 cells and primary hamster hepatocytes. Cultured cells were incubated with different doses of simvastatin (0.1-10 microM) for a period of 18 h. A dose-dependent increase in synthesis and secretion of apoAI was observed in both cell types. There was a significant increase in the synthesis of apoAI in HepG2 cells (44.3+/-12.1%), and hamster hepatocytes (212+/-2%) after treatment with 10 microM of the statin. The increase in apoAI synthesis appeared to result in a higher level of apoAI secreted into the culture media in both cell types (49.2+/-7.8% in HepG2, 197+/-0.2% in hamster hepatocytes). ApoAI mRNA levels were also significantly increased in both cell types in response to statin treatment. Control experiments with transferrin confirmed specificity of the effect on apoAI secretion. Analysis of a density fraction containing HDL particles in culture media revealed an increase in HDL-associated apoAI of 94.3+/-2.1% in HepG2 cells and 27.0+/-0.03% in hamster hepatocytes following 10 microM simvastatin-treatment. Comparative studies of simvastatin and lovastatin indicated a differential ability to induce apoAI synthesis and secretion, with simvastatin having a more significant effect. Thus, acute statin treatment of cultured hepatocytes (transformed as well as primary) resulted in a significant upregulation of apoAI mRNA and apoAI synthesis, causing oversecretion of apoAI and HDL extracellularly. The stimulatory effect on apoAI synthesis and secretion may thus explain the clinical observation of an elevated plasma HDL-cholesterol level in hyperlipidemic patients treated with certain statins.

Animals↗
PubMed2003

Adenovirus-mediated gene transfer of a secreted decoy human macrophage scavenger receptor (SR-AI) in LDL receptor knock-out mice.

Macrophage scavenger receptors (MSR) play an important role in the pathogenesis of atherosclerosis. Therefore, modulation of MSR activity could have a beneficial effect on atherogenesis. One way to antagonize the function of a cell surface scavenger receptor is to use a soluble decoy receptor. We have constructed a soluble, chimaeric fusion protein that consists of the bovine growth hormone signal sequence and the human MSR AI extracellular domains. This secreted decoy MSR (sMSR) was cloned into an adenoviral vector and the recombinant adenoviruses were used for gene transfer experiments in vivo. We have previously shown that the secreted MSR inhibits degradation of acetylated LDL and oxidized LDL in mouse macrophages and reduces foam cell formation in vitro. We now report that in comparison to LacZ transfected control mice gene transfer with sMSR adenoviruses via tail vein injection (1 x 10(9) pfu) reduces atherosclerotic lesion area in hypercholesterolemic LDL receptor knock-out mice by 14 (P<0.05) and 19% (P=0.01), 4 and 6 weeks after the gene transfer. However, a statistically significant difference in the aortic root atherosclerosis was not detected. This is the first demonstration that the decoy sMSR can affect atherogenesis in mice after recombinant adenovirus-mediated gene transfer. Even though the achieved reduction in atherosclerosis was relatively modest the results suggest that sMSR may offer new strategies for the treatment of atherosclerosis and lipid accumulation in the vessel wall.

Adenoviridae↗