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Biomedical subjects

Xiaofei Wang

Publications and source records attributed to Xiaofei Wang.

At least 37 records · Page 2Linked to original sources
PubMed2005

In vivo imaging of retinoic acid receptor beta2 transcriptional activation by the histone deacetylase inhibitor MS-275 in retinoid-resistant prostate cancer cells.

BACKGROUND: In retinoid resistant epithelial tumors, the lack of retinoic acid receptor beta2 (RARbeta2) expression due to epigenetic silencing impairs the activation of retinoid target genes including RARbeta2, and has been associated with the development of cancer. In this study we developed a strategy to monitor the re-activation of RARbeta2 by chromatin remodeling agents combined with retinoids in real time, and to correlate the RARbeta2 re-activation with anti-tumor activity. METHODS: We selected the RARbeta2-negative retinoid resistant human prostate carcinoma cell line PC3 and stably transfected it with a luciferase expression vector under the control of a functional segment of RARbeta2 promoter (pGL2-RARbeta2-PC3). Then, we used the bioluminescence technology to monitor the reporter gene expression in real time both in vitro and in vivo following combination treatment with the histone deacetylase inhibitor MS-275 and 13-cis retinoic acid (CRA). Based on the effective dose for the RARbeta2 re-activation, we tested the anti-tumor activity of this drug combination. RESULTS: Following combination treatment with MS-275 and CRA, we observed endogenous RARbeta2 re-expression, acetylation at the RARbeta2 promoter level, and synergistic activation of the luciferase reporter gene by real time imaging both in vitro and in vivo. Combination treatment with MS-275 and CRA restored retinoid sensitivity in human prostate carcinoma cell lines, and had a greater inhibitory effect on tumor cell growth than single agents in vitro and in vivo. CONCLUSIONS: This study provides evidence that HDAC inhibitors restore retinoid sensitivity in prostate cancer cells, and in vivo real time imaging of RARbeta2 activation may represent a useful tool to study the pharmacodynamics of combination therapy with HDAC inhibitors and retinoids.

Animals↗
PubMed2005

Enhanced aortic atherosclerosis in transgenic Watanabe heritable hyperlipidemic rabbits expressing lipoprotein lipase.

OBJECTIVE: This study was designed to address the effects of increased lipoprotein lipase (LPL) activity on atherosclerosis in the setting of LDL receptor deficiency. METHODS: We generated transgenic (Tg) Watanabe heritable hyperlipidemic (WHHL) rabbits overexpressing human LPL and compared their plasma lipids and aortic atherosclerosis with non-Tg WHHL rabbits. RESULTS: Increased expression of LPL significantly ameliorated hypertriglyceridemia and hypercholesterolemia in Tg WHHL rabbits [64% reduction in total cholesterol (TC) and 91% reduction in triglycerides (TG) vs. non-Tg]. In spite of this beneficial effect of LPL, Tg WHHL rabbits had two-fold greater aortic atherosclerosis than non-Tg WHHL rabbits. Analysis of plasma lipoprotein profiles revealed that increased LPL activity in Tg WHHL rabbits resulted in the dramatic reduction of large TG-rich lipoproteins (VLDL, d<1.006 g/ml and IDL, d=1.006-1.02) but concomitant increases in LDL fractions, especially those of small and dense LDL particles (d=1.04-1.06, 2.6-fold over non-Tg). Using apoB-containing lipoproteins, we found that small-sized LDL from Tg WHHL rabbits contained more oxidizable substrate and exhibited higher affinity to biglycan than large TG-rich LDL of non-Tg WHHL rabbits. CONCLUSIONS: We conclude that in the absence of LDL receptor function, increased LPL activity accelerates the catabolism of large TG-rich VLDL (possibly via the LRP pathway) and subsequently improves hyperlipidemia. However, LPL may also enhance the generation and accumulation of small dense LDLs, which are more atherogenic.

Animals↗
PubMed2005

Predominant constitutive CFTR conductance in small airways.

BACKGROUND: The pathological hallmarks of chronic obstructive pulmonary disease (COPD) are inflammation of the small airways (bronchiolitis) and destruction of lung parenchyma (emphysema). These forms of disease arise from chronic prolonged infections, which are usually never present in the normal lung. Despite the fact that primary hygiene and defense of the airways presumably requires a well controlled fluid environment on the surface of the bronchiolar airway, very little is known of the fluid and electrolyte transport properties of airways of less than a few mm diameter. METHODS: We introduce a novel approach to examine some of these properties in a preparation of minimally traumatized porcine bronchioles of about 1 mm diameter by microperfusing the intact bronchiole. RESULTS: In bilateral isotonic NaCl Ringer solutions, the spontaneous transepithelial potential (TEP; lumen to bath) of the bronchiole was small (mean +/- sem: -3 +/- 1 mV; n = 25), but when gluconate replaced luminal Cl-, the bionic Cl- diffusion potentials (-58 +/- 3 mV; n = 25) were as large as -90 mV. TEP diffusion potentials from 2:1 NaCl dilution showed that epithelial Cl- permeability was at least 5 times greater than Na+ permeability. The anion selectivity sequence was similar to that of CFTR. The bionic TEP became more electronegative with stimulation by luminal forskolin (5 microM)+IBMX (100 microM), ATP (100 microM), or adenosine (100 microM), but not by ionomycin. The TEP was partially inhibited by NPPB (100 microM), GlyH-101* (5-50 microM), and CFTRInh-172* (5 microM). RT-PCR gave identifying products for CFTR, alpha-, beta-, and gamma-ENaC and NKCC1. Antibodies to CFTR localized specifically to the epithelial cells lining the lumen of the small airways. CONCLUSION: These results indicate that the small airway of the pig is characterized by a constitutively active Cl- conductance that is most likely due to CFTR.

Animals↗
PubMed2005

Path concentration distribution of toluene using remote sensing FTIR and one-dimensional reconstruction method.

A one-dimensional mapping technique coupled with Open-Path remote sensing FTIR was presented in this article. This technique was applied to one of the air toxic volatile organic compounds (VOCs)-toluene. The Path Integrated Concentrations (PICs) of toluene in different path lengths along one beam path were fitted by polynomial fitting method with degrees from 3 to 7. The 6th degree polynomial fitting showed the best fitting result. Moreover, the methods of reconstructing path concentration distribution along the beam path by applying a Gaussian model and the derivative of 6th degree polynomial fitting function were established in this article. The reconstructed concentrations of toluene along the beam path by the two methods were experimentally close. Results showed that the concentration peaks were at 1.05 and 2.40 m from the instrument by applying the Gaussian model with the maximum concentration of 0.85 and 3.19 ppm, and at 0.99 and 2.49 m from the instrument with the maximum concentration of 0.78 and 2.80 ppm by applying the 6th polynomial fitting function. It was obvious that the reconstruction results by these two methods were very close. This approach could be appreciated for its fast calculation, exact peak location orientation and concentration flow tendency mapping. In can be concluded that this method can provide the path concentration distributions of much more releasing gases in a briefly and intuitionistic way. The remote sensing FTIR coupled with these mathematical reconstruction techniques can be applied to the real world environmental and industrial hygiene monitoring, thus works as an alert system for the VOCs pollution.

Air Pollutants↗
PubMed2005

Reconstruction of air contaminant concentration distribution in a two-dimensional plane by computed tomography and remote sensing FTIR spectroscopy.

This research combined open path FTIR (OP-FTIR) technique and computed tomography (CT) to reconstruct air contaminant concentration distribution in a two-dimensional plane. Remote sensing FTIR instrument was used to scan radial beam geometry and obtain path integrated concentration (PIC) data of acetone gas in the measuring plane. Smooth basis function minimization (SBFM) algorithm was adopted to reconstruct gaseous concentration distribution. For the purpose of finding out the preferable number of Gaussians used in SBFM algorithm, single-Gaussian, double-Gaussian, and three-Gaussian models were used respectively. Experimental results showed that the reconstruction result of acetone concentration distribution by SBFM algorithm with double-Gaussian model agreed with real distribution more qualitatively and quantitatively than single-Gaussian and three-Gaussian. Also, it has been proved that simulated annealing algorithm used in the optimization process of SBFM reconstruction was feasible and effective. Although computed tomography and remote sensing FTIR technique (CT-RS-FTIR) is still at the laboratory study stage, with further improvement of SBFM algorithm and beam geometry, it promises to be used in air pollution monitoring widely.

Acetone↗
PubMed2005

Role of nonfeminizing estrogens in brain protection from cerebral ischemia: an animal model of Alzheimer's disease neuropathology.

Estrogens are potent and efficacious neuroprotectants both in vitro and in vivo in a variety of models of neurotoxicity. We determined the structural requirements for neuroprotection in in vitro assays using a library of more than 70 novel estratrienes, synthesized to reduce or eliminate estrogen receptor (ER) binding. We observed that neuroprotection could be enhanced by as much as 200-fold through modifications that positioned a large, bulky group at the C2 and/or C4 position of the phenolic A ring of the estratriene. Further, substitutions on the B, C, or D rings either reduced or did not markedly change neuroprotection. For this library of compounds, there was a negative correlation between ER binding and neuroprotection, as the more potent compounds showed weaker or no ER binding. In an in vivo model for neuroprotection, transient cerebral ischemia, efficacious compounds were active in protection of brain tissue from this pro-oxidant insult. Finally, estradiol protected brains from insult-induced Alzheimer's disease (AD) neuropathology, including activation of apoptosis, stimulation of Abeta production, hyperphosphorylation of tau, activation of cyclin-dependent kinases, and activation of catastrophic attempts at neuronal mitosis. Collectively, these results demonstrate that nonfeminizing estrogens are neuroprotective and protect the brain from the induction of AD-like neuropathology in an animal model. These features of nonfeminizing estrogens make them attractive compounds for assessment of efficacy in AD and stroke, because they are not expected to show the side effects of chronic estrogen therapy that are ER mediated in the liver, uterus, and breast.

Alzheimer Disease↗
PubMed2005

Mitochondria play a central role in estrogen-induced neuroprotection.

Oxidative stress, bioenergetic impairment and mitochondrial failure have all been implicated in the etiology of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD), as well as retinal degeneration in glaucoma and retinitis pigmentosa. Moreover, at least 75 debilitating, and often lethal, diseases are directly attributable to deletions or mutations in mitochondrial DNA, or in nuclear-encoded proteins destined for delivery to the mitochondria. Such widespread mitochondrial involvement in disease reflects the regulatory position mitochondrial failure plays in both acute necrotic cell death, and in the less catastrophic process of apoptosis. The potent feminizing hormone, 17 beta-estradiol (E2), has shown cytoprotective activities in a host of cell and animal models of stroke, myocardial infarct and neurodegenerative diseases. The discovery that 17alpha-estradiol, an isomer of E2, is equally as cytoprotective as E2 yet is >200-fold less active as a hormone, has permitted development of novel, more potent analogs where cytoprotection is independent of hormonal potency. Studies of structure-activity-relationships, glutathione interactions and mitochondrial function have led to a mechanistic model in which these steroidal phenols intercalate into cell membranes where they block lipid peroxidation reactions, and are in turn recycled via glutathione. Such a mechanism would be particularly germane in mitochondria where function is directly dependent on the impermeability of the inner membrane, and where glutathione levels are maintained at extraordinarily high 8-10mM concentrations. Indeed, the parental estrogens and novel analogs stabilize mitochondria under Ca(2+) loading otherwise sufficient to collapse membrane potential. The cytoprotective and mitoprotective potencies for 14 of these analogs are significantly correlated, suggesting that these compounds prevent cell death in large measure by maintaining functionally intact mitochondria. This therapeutic strategy is germane not only to sudden mitochondrial failure in acute circumstances, such as during a stroke or myocardial infarction, but also to gradual mitochondrial dysfunction associated with chronic degenerative disorders such as AD, PD and HD.

Animals↗
PubMed2005

Estrogens as protectants of the neurovascular unit against ischemic stroke.

Estrogens are now recognized as potent neuroprotectants in a variety of in vitro and in vivo model for cerebral ischemia. These protective effects of estrogens are seen in neurons, astrocytes, microglia and vascular endothelial cells and result in a profound protection of the brain during stroke. Herein, we provide a thesis that indicates that the protective effects of estrogens during stroke may be a combined effect on multiple targets of the neurovascular unit (NVU) through a fundamental protective effect of estrogens on the subcellular organelle that defines the fate of cells during insults, the mitochondria. By protecting mitochondria during insult, estrogens are able to reduce or eliminate the signal for cellular necrosis or apoptosis and thereby protect the NVU from ischemia/reperfusion. In this context, estrogens may be unique in their ability to target the cellular site of initiation of damage during stroke and could be a central compound in a multi-drug approach to the prevention and treatment of brain damage from stroke.

Animals↗
PubMed2005

Patient preference in a crossover clinical trial of patients with osteoarthritis of the knee or hip: face validity of self-report questionnaire ratings.

OBJECTIVE: To analyze correlational validity of self-report responses regarding patient preference between 2 drugs at the conclusion of a crossover double-blind clinical trial in patients with osteoarthritis (OA) of the knee or hip. METHODS: Patients were randomized to 6 weeks' treatment of diclofenac/misoprostol or acetaminophen, followed by crossover to 6 weeks of the other drug. Patient preference was queried at the final visit: "Please compare control of your arthritis during the first and second periods as 'much better' or 'better' in the first period, 'no different' or 'better' or 'much better' in the second period." Patient preference ratings were evaluated in comparisons with 4 independent self-report measures within each treatment period: (1) change in Western Ontario McMaster (WOMAC) questionnaire scores; (2) change in pain visual analog scale (VAS) on a multidimensional Health Assessment Questionnaire (MDHAQ); (3) patient ratings of drug efficacy; and (4) patient report of change in arthritis status, as well as investigator ratings of the more efficacious drug. RESULTS: Among 173 patients, diclofenac/misoprostol was rated as "much better" by 54 and "better" by 45, acetaminophen was rated as "better" by 18 and "much better" by 17, and "no difference" by 39 patients. Spearman rank correlations for patient preferences were significant for changes in WOMAC scores, pain VAS, and independent patient ratings of drug efficacy and changes in arthritis status within each treatment period, as well as with physician ratings of the more efficacious drug (p < 0.001). CONCLUSION: Significant correlational validity is documented for patient self-report of preferences between 2 drugs compared to independent measures within each treatment period in this crossover clinical trial in patients with OA of the knee or hip.

Acetaminophen↗
PubMed2005

[Study on purification of total peony glycoside with D140 macroporous resin].

OBJECTIVE: To study the extraction process of total peony glycoside from Paeonia veitchii Lynvh. METHODS: The extraction process of total peony glycoside with D140 macroporous resin adsorbent was selected with different condence of ethanol for gradient elution. RESULTS: The optimum condence was 35% ethanol. CONCLUSION: The extraction ratio of paeoniflorin was >50%, and the extraction process is simple and convenient. The regenaration of resin is easy, this method is advisible.

Chromatography, High Pressure Liquid↗
PubMed2004

Macrophage-derived lipoprotein lipase increases aortic atherosclerosis in cholesterol-fed Tg rabbits.

Lipoprotein lipase (LPL) produced by macrophages is upregulated in the atherosclerotic lesions; however, it is not fully understood whether increased macrophage-derived LPL is pro-atherogenic. To examine the hypothesis that macrophage-derived LPL in the arterial wall enhances atherosclerotic lesion formation, we generated transgenic (Tg) rabbits that express the human LPL transgene under the control of the human scavenger receptor enhancer/promoter, which drives macrophage-specific expression of the human LPL gene. We fed Tg and non-Tg littermate rabbits a diet containing 0.3% cholesterol for 16 weeks and compared their lipoproteins and aortic atherosclerosis. We found that there was no difference in plasma lipid or lipoprotein profiles between Tg and non-Tg rabbits; however, atherosclerotic lesions were significantly increased in Tg compared to non-Tg rabbits. There was a 1.4-fold increase in total aortic en face lesions and a 2-fold increase in intimal lesions evaluated by image analysis system. Furthermore, immunohistochemical staining revealed that the increased atherosclerotic lesions present in Tg rabbits were characterized by marked accumulation of macrophage-derived foam cells and frequently associated with the deposition of oxidized LDL. These results support the notion that macrophage-derived LPL in the arterial wall is pro-atherogenic, possibly via the enhancement of foam cell formation during atherogenesis.

Animals↗
PubMed2004

The histone deacetylase inhibitor NVP-LAQ824 inhibits angiogenesis and has a greater antitumor effect in combination with the vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584.

Chromatin remodeling agents such as histone deacetylase inhibitors have been shown to modulate gene expression in tumor cells and inhibit tumor growth and angiogenesis. Vascular endothelial growth factor (VEGF) and VEGF receptors represent critical molecular targets for antiangiogenesis therapy. In this study, we investigated the biological effect of the histone deacetylase inhibitor NVP-LAQ824 in combination with the VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 on tumor growth and angiogenesis. We report that treatment with NVP-LAQ824 affected tumor and endothelial cells and was associated with increased histone acetylation, p21 up-regulation, and growth inhibition. In addition, NVP-LAQ824 treatment inhibited the expression of angiogenesis-related genes such as angiopoietin-2, Tie-2, and survivin in endothelial cells and down-regulated hypoxia-inducible factor 1-alpha and VEGF expression in tumor cells. Combination treatment with NVP-LAQ824 and PTK787/ZK222584 was more effective than single agents in inhibiting in vitro and in vivo VEGF-induced angiogenesis. Endothelial cell proliferation, tube formation, and invasion into the Matrigel plugs were reduced. In mouse models with established subcutaneous prostate (PC3) and orthotopic breast tumors (MDA-MB321), this combination treatment induced 80 to 85% inhibition of tumor growth without overt toxicity. These results suggest that the combination of histone deacetylase inhibitors and VEGF receptor inhibitors may target multiple pathways in tumor progression and angiogenesis and represents a novel therapeutic approach in cancer treatment.

Angiogenesis Inhibitors↗
PubMed2004

Duplicated Spot 14 genes in the chicken: characterization and identification of polymorphisms associated with abdominal fat traits.

In mammals, thyroid hormone responsive Spot 14 (THRSP) is a small acidic protein that is predominately expressed in lipogenic tissue (i.e., liver, abdominal fat and the mammary gland). This gene has been postulated to play a role in lipogenesis, since it responds to thyroid hormone stimulation, high glucose levels and it is localized to a chromosomal region implicated in obesity. In this paper, we report the identification and characterization of duplicated polymorphic paralogs of Spot 14 in the chicken, THRSPalpha and THRSPbeta. Despite low similarity in amino acid (aa) sequence between chickens and mammals, other properties of Spot 14 (i.e., pI, subcellular localization, transcriptional control and functional domains) appear to be highly conserved. Furthermore, a synteny group of THRSP and its flanking genes [NADH dehydrogenase (NDUFC2) and glucosyltransferase (ALG8)] appears to be conserved among chickens, humans, mice and rats. Polymorphic alleles, involving a variable number of tandem repeats (VNTR), were discovered in the putative protein coding region of the duplicated chicken THRSPalpha (9 bp) and THRSPbeta (6 or 12 bp) genes. Our study shows that the THRSPalpha locus is associated with abdominal fat traits in a broilerxLeghorn resource population.

Adipose Tissue↗
PubMed2004

Association of increased expression of macrophage elastase (matrix metalloproteinase 12) with rheumatoid arthritis.

OBJECTIVE: Increased enzymatic activity of matrix metalloproteinases (MMPs) may promote the progression of rheumatoid arthritis (RA). We undertook this study to investigate the expression and localization of human macrophage elastase (MMP-12) in synovial tissue from RA patients and to compare MMP-12 levels in the synovial tissue and synovial fluid of RA patients with the corresponding levels in patients with osteoarthritis (OA). METHODS: We obtained synovial tissues from 23 RA patients and 29 OA patients and analyzed MMP-12 expression using immunohistochemistry, Western and Northern blotting analyses, and zymography. Furthermore, we quantified MMP-12 levels in synovial fluid by Western blotting and zymography. RESULTS: Northern blotting analysis demonstrated that RA synovial tissue contained higher levels of MMP-12 messenger RNA than did OA synovial tissue. Western blotting revealed that MMP-12 proteins were consistently and markedly increased in RA synovial tissue compared with OA synovial tissue. A greater amount of immunoreactive proteins corresponding to catalytic forms of MMP-12 was present in RA synovial tissue and synovial fluid, and the MMP-12 proteins exhibited caseinolytic activity in vitro. Immunohistochemical staining showed that the major cells expressing MMP-12 were synovial lining cells, many of which were inflammatory macrophages. CONCLUSION: These results establish a possible mechanism by which macrophage-derived MMP-12 may play an important role in the destructive process in RA. Inhibition of MMP-12 may be a potential modality for the treatment of RA.

Arthritis, Rheumatoid↗
PubMed2004

Overexpression of human matrix metalloproteinase-12 enhances the development of inflammatory arthritis in transgenic rabbits.

Increased proteolytic activity of matrix metalloproteinases (MMPs) may promote articular destruction such as occurs in rheumatoid arthritis and osteoarthritis. Recently, we reported that synovial tissue and fluid obtained from patients with rheumatoid arthritis contained higher activity of macrophage elastase (MMP-12). To examine the hypothesis that MMP-12 may potentially enhance the progression of arthritis, we investigated the effects of overexpression of MMP-12 on inflammatory arthritis in transgenic rabbits that express the human MMP-12 transgene in the macrophage lineage. Inflammatory arthritis was produced by articular injection of carrageenan solution and the degree of inflammatory arthritis in transgenic rabbits was compared with that in control rabbits. We found that overexpression of MMP-12 in transgenic rabbits significantly enhanced the arthritic lesions, resulting in severe synovial thickening, pannus formation, and prominent macrophage infiltration at an early stage and a marked destruction of articular cartilage associated with loss of proteoglycan at a later stage. These results demonstrate that excessive MMP-12 expression exacerbates articular connective tissue and cartilage degradation and thus plays a critical role in the development of inflammatory joint disease.

Animals↗
PubMed2004

Macrophage-specific overexpression of human matrix metalloproteinase-12 in transgenic rabbits.

Increased matrix metalloproteinase-12 (MMP-12) has been implicated in atherosclerosis and many other inflammatory processes. To define MMP-12 functions in vivo, we generated transgenic rabbits that expressed human (h) MMP-12 gene under the control of a macrophage-specific promoter, the human scavenger receptor promoter. Two transgenic founder rabbits were found to have hMMP-12 transgene integration by Southern blot analysis. hMMP-12 mRNA was expressed in peritoneal and alveolar macrophages, and in tissues enriched in macrophages in transgenic rabbits. High levels of hMMP-12 protein were detected in the conditioned media of cultured peritoneal and alveolar macrophages from transgenic rabbits. Zymography showed that hMMP-12 secreted from macrophages possessed enzymatic activity toward beta-casein. To evaluate the expression of hMMP-12 in inflammatory sites, we used carrageenan-induced granulomas as an in vivo model for tissue macrophages and foam cells. Granuloma size in transgenic rabbits was significantly increased compared to that in control rabbits, and histological examination revealed that granulomas of transgenic rabbits were enriched in macrophages associated with increased hMMP-12 expression. We believe that this transgenic rabbit model with increased expression of hMMP-12 may become a useful model for further mechanistic studies of MMP-12 in inflammatory diseases and cancer invasion; it is also an ideal model for testing the in vivo action of MMP-12 inhibitors.

Animals↗
PubMed2004

Overexpression of lipoprotein lipase in transgenic rabbits leads to increased small dense LDL in plasma and promotes atherosclerosis.

Lipoprotein lipase (LPL) is a key enzyme in the hydrolysis of triglyceride-rich lipoproteins. Previous studies using transgenic mice and rabbits have demonstrated that high level of LPL activity in adipose and skeletal muscle protects against diet-induced hypercholesterolemia and subsequently prevents aortic atherosclerosis. However, it is unknown, per se, whether increased LPL activity itself is antiatherogenic, or whether the antiatherogenic effect of LPL is dependent upon the LPL lipid-lowering effect. To address this issue, we fed LPL transgenic and littermate rabbits diets containing different amounts of cholesterol (0.3-0.6%) adjusted to maintain their plasma cholesterol concentrations at similarly high levels for 16 weeks. We analyzed their lipoprotein profiles and compared their susceptibility to atherosclerosis. The results showed that the overexpression of LPL in transgenic rabbits reduced remnant lipoproteins (beta-VLDL, d<1.006 g/ml) but concomitantly led to a significant increase of the large (d=1.02-1.04 g/ml) and small LDLs (d=1.04-1.06 g/ml) compared to the amounts in control rabbits. Furthermore, we found that with equally high hypercholesterolemia, transgenic rabbits developed 1.8-fold more extensive aortic atherosclerosis than control rabbits. To examine the hypothesis that altered lipoprotein profiles may be responsible for the enhanced atherosclerosis in transgenic rabbits, we studied the atherogenic properties of apoB-containing lipoproteins in vitro. These studies revealed that small-sized LDLs of transgenic rabbits were more susceptible to copper-induced oxidation and had higher affinity to biglycan than large remnant lipoproteins. We conclude, therefore, that LPL exerts a dual function in terms of its atherogenicity, namely antiatherogenicity, through enhancing receptor-mediated remnant lipoprotein catabolism and proatherogenicity via the generation of a large amount of small-sized LDLs. At an equal atherogenic-cholesterol level, small and dense LDLs are more atherogenic than large remnant lipoproteins.

Animals↗