Cholesterol and atherosclerosis.
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ATP-Binding Cassette Transporters↗
Biomedical subjects
M Aikawa
Publications and source records attributed to M Aikawa.
Lipid lowering improves endothelial functions.
The healthy endothelium usually provides an anticoagulant, vasodilatory and anti-inflammatory spectrum of functions that are central in vascular homeostasis. Dysfunction of the endothelium is a common feature of all phases of atherosclerosis. Hypercholesterolemia provokes many aspects of endothelial dysfunction before and during the development of atheroma. For example, a high cholesterol diet leads to the formation of a fatty streak and the recruitment and binding of blood leukocytes to the artery wall. This process requires expression by the endothelial cells of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1). In rabbits that are fed an atherogenic diet, the aortic endothelium, which usually expresses little VCAM-1, shows foci of VCAM-1 expression soon after initiating this diet. Furthermore, lowering plasma cholesterol by diet or drugs down-regulates the expression of VCAM-1 and reduces the density of inflammatory cells in the atherosclerotic plaque. Hypercholesterolemia also attenuates normal vasodilatation to several stimuli such as exercise and acetylcholine. In healthy subjects, the vascular endothelium produces the vasodilator nitric oxide. In atherosclerosis, however, nitric oxide bioavailability is impaired. As a result, atherosclerotic coronary arteries commonly display a vasoconstrictor response when challenged with acetylcholine. Lipid lowering appears to favorably influence endothelial vasomotor and inflammatory functions in ways that may benefit patients with coronary artery disease. Continued probing of the basic mechanisms of endothelial dysfunction and its treatment may lead to new therapies that offer clinical benefits in patients with atherosclerosis, including reductions in coronary events.
Animals↗
Attachment of Moraxella catarrhalis occurs to the positively charged domains of pharyngeal epithelial cells.
Attachment of bacteria to host cells is the initial step in the pathogenesis of infection. Several factors, such as hydrophobicity, surface electric charge, and van der Waals force, are considered to be responsible for the attachment step. However, it is not clear why bacteria and epithelial cells, both of which possess a negative surface charge, do not repel one another. In the present study, we used Moraxella catarrhalis and pharyngeal epithelial cells to study the surface charges of structures involved in the attachment. By atomic force microscopy (AFM) equipped with surface potential spectroscopy, it was found that the cell surface microplicae have a positive charge of 30.1+/-3.6 mV (mean+/-SE). The depressions between the microplicae have a negative surface charge of 43.5+/-4.0 mV. Using cationic ferritin and electron microscopy (EM) we confirmed that the depressions between the microplicae have a negative charge. By AFM and by using cationic ferritin with EM, it was found that the net surface charge of the bacterial cells is negative. By both AFM and EM, it was found that the bacterial cells attach to the microplicae of the pharyngeal epithelial cell. Our work confirmed the general belief that both kinds of cells do have a net negative charge. We conclude that there are positively and negatively charged domains on the surface of human pharyngeal epithelial cells. M. catarrhalis evidently attaches to the positively charged domain (i.e. microplicae) of pharyngeal epithelial cells.
Adult↗
Age-related dopamine deficiency in the mesostriatal dopamine system of zitter mutant rats: regional fiber vulnerability in the striatum and the olfactory tubercle.
Oxidant stress has been implicated in the pathogenesis of Parkinson's disease. To test the oxidant stress hypothesis of dopaminergic degeneration, age-related changes in the mesostriatal dopamine neuron system were compared between zitter mutant rats which have abnormal metabolism of oxygen species in the brain and Sprague-Dawley rat as a control using the neurochemistry and immunohistochemistry. Dopamine content in the caudate-putamen, nucleus accumbens and olfactory tubercle of zitter rats decreased significantly with age, and was lower than that found in corresponding age-matched controls. In the zitter rats, the reduction of dopamine was more prominent in the caudate-putamen than in the nucleus accumbens and olfactory tubercle. A characteristic decline of tyrosine hydroxylase-immunoreactive fibers in the caudate-putamen of the zitter rat was also observed. In the dorsolateral caudate-putamen, reduction of tyrosine hydroxylase-immunoreactive fibers was observed in the matrix-like area, whereas in the ventromedial caudate-putamen the reduction occurred in the patch-like areas. Degeneration of tyrosine hydroxylase-immunoreactive fibers which was characterized by swollen varicosities and clustered fibers was observed in the caudate-putamen and nucleus accumbens and preceded loss of normal tyrosine hydroxylase-immunoreactive fibers in the caudate-putamen. Thus, the depletion of dopamine in the terminal areas is related to axonal degeneration. However, there was no degenerative tyrosine hydroxylase-immunoreactive fibers in the olfactory tubercle at any examined age, but reductions of tyrosine hydroxylase-immunoreactive fibers and dopamine contents were noted in the olfactory tubercle after four months-of-age. Since the zitter rats have an abnormal oxygen metabolism, the degeneration of tyrosine hydroxylase-immunoreactive fibers could result from an accumulation of superoxide species. The present results provide support for the oxidant stress hypothesis of dopaminergic neuronal degeneration and further indicate the region-specific vulnerability of the nigrostriatal dopamine system.
3,4-Dihydroxyphenylacetic Acid↗
Attenuation of KATP channel-opener induced shortening of repolarization time by alpha 1-adrenoceptor antagonist during ischemia in canine heart.
The purpose of the study was to determine whether a new KATP channel opener, Y 26763 (Y), can influence the electrophysiological properties in the ischemic myocardium as well as to determine whether the blunting effect of the alpha 1-adrenoceptor antagonist bunazosin (BN) on an ischemia-induced shortening of repolarization time can be related to the KATP channel activity. The anterior descending branch of the left coronary artery was ligated four times for 5 minutes, separated by 15 minutes of reperfusion (stages 1-4) to test the dose-dependent effect of drugs on repolarization. Dogs received either vehicle (n = 9), Y (0.4, 2.0, and 4.0 micrograms/kg at stages 2, 3, and 4, respectively, with 0.4 microgram/kg/min drip infusion at each of stages 2-4, n = 7), BN (0.1 mg at each of stages 2-4, n = 8), or a combination of these two drugs (BN + Y, the same dose of BN and Y in groups BN and Y, respectively, n = 9). Drugs were administered into the left atrium. The monophasic action potential (MAP) and regional electrograms were recorded. The MAP90 and the duration of the slow deflections (DSD) of the regional electrogram were used as markers of repolarization. The Vmax of the MAP and the rapid deflections (DRD) of the regional electrogram were used as markers of conduction. Y augmented an ischemia-induced shortening of MAP90 and DSD in proportion to an increase in the dose given and the plasma concentration (P < .05-.01), especially at the epicardial site. BN and BN + Y blunted the ischemia-related shortening of MAP90 and DSD, causing a reduction in repolarization time dispersion between the ischemic and normal zones. There were no significant changes in the Vmax or DRD in the ischemic zone between periods before and after an increase in each drug dose in the four groups. None of the seven dogs developed ventricular tachycardia (VT)/ventricular fibrillation (VF) in the Y group, whereas two of the eight dogs in the BN group, three of the nine dogs in the BN + Y group, and three of the nine dogs in the control group developed VT/VF. These results suggest that the alpha 1-adrenergic blocker bunazosin blunts the shortening effect of KATP channel activator on repolarization time, and that the KATP channel opener Y may be antiarrhythmic, although the repolarization time dispersion during myocardial ischemia is increased.
ATP-Binding Cassette Transporters↗
Lipid lowering reduces proteolytic and prothrombotic potential in rabbit atheroma.
Thrombus formation at sites of atheromatous plaque disruption cause most acute coronary events such as myocardial infarction and unstable angina. Lesional macrophages and smooth muscle cells produce matrix metallo-proteinases (MMPs) and tissue factor (TF), the molecules likely contribute to plaque rupture and thrombus formation. Recent clinical studies have suggested that lipid lowering can reduce the incidence of acute coronary events. We have recently determined the effects of long-term dietary lipid lowering on atheroma of high-cholesterol-fed rabbits. Lipid lowering diminished macrophage accumulation, reduced expression and activity of MMPs, and increased interstitial collagen accumulation in rabbit atheroma. Expression and activity of TF in atheroma also substantially decreased during lipid lowering. Dietary lipid lowering also promoted accumulation of mature smooth muscle cells expressing less MMPs and TF in the plaque's fibrous cap. These results suggest potential mechanisms by which lipid lowering reduces acute coronary events in patients by decreasing proteolytic and prothrombotic activity within the atheroma.
Animals↗
Malaria infection induces rapid elevation of the soluble Fas ligand level in serum and subsequent T lymphocytopenia: possible factors responsible for the differences in susceptibility of two species of Macaca monkeys to Plasmodium coatneyi infection.
The intraerythrocytic stage of the simian malaria parasite Plasmodium coatneyi (CDC strain) was intravenously inoculated into two species of macaques with different susceptibilities to infection with this parasite, including four Japanese macaques (Macaca fuscata) and three cynomolgus macaques (M. fascicularis). The Japanese macaques infected with P. coatneyi developed severe clinical manifestations similar to those of severe human malaria and eventually became moribund, while the infected cynomolgus macaques, natural hosts of the parasite, exhibited no severe manifestation of disease except anemia and finally recovered from the infection. In the infected Japanese macaques, peripheral CD4(+) and CD8(+) T-cell populations were markedly decreased and fragmentation of chromosomal DNA in peripheral blood mononuclear cells was detected during the terminal period of infection, suggesting that apoptotic cell death was responsible at least in part for the T lymphocytopenia. Furthermore, soluble Fas ligand levels in sera of the infected Japanese macaques increased gradually to a markedly high level of 28. 83 +/- 10.56 pg/ml (n = 4) when the animals became moribund. On the other hand, none of the infected cynomolgus monkeys exhibited either T lymphocytopenia or elevated soluble Fas ligand level. These findings suggest that differences in immune response between the two species of macaque tested accounted for the contrasting outcomes after infection with the same isolate of malarial parasite, and in particular that a profound T lymphocytopenia due to Fas-derived apoptosis played a role in the fatal course of malaria in the infected Japanese macaques.
Animals↗
Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction.
Matrix metalloproteinase-9 (MMP-9) is prominently overexpressed after myocardial infarction (MI). We tested the hypothesis that mice with targeted deletion of MMP9 have less left ventricular (LV) dilation after experimental MI than do sibling wild-type (WT) mice. Animals that survived ligation of the left coronary artery underwent echocardiographic studies after MI; all analyses were performed without knowledge of mouse genotype. By day 8, MMP9 knockout (KO) mice had significantly smaller increases in end-diastolic and end-systolic ventricular dimensions at both midpapillary and apical levels, compared with infarcted WT mice; these differences persisted at 15 days after MI. MMP-9 KO mice had less collagen accumulation in the infarcted area than did WT mice, and they showed enhanced expression of MMP-2, MMP-13, and TIMP-1 and a reduced number of macrophages. We conclude that targeted deletion of the MMP9 gene attenuates LV dilation after experimental MI in mice. The decrease in collagen accumulation and the enhanced expression of other MMPs suggest that MMP-9 plays a prominent role in extracellular matrix remodeling after MI.
Animals↗
Contrasting functions of IgG and IgE antimalarial antibodies in uncomplicated and severe Plasmodium falciparum malaria.
Plasmodial infection results in a significant elevation of the blood concentrations of immunoglobulins including IgE. Two well-characterized groups of adult Thai patients with either uncomplicated or severe Plasmodium falciparum malaria were studied over a period of four weeks. The mean parasitemias were approximately three-fold higher in patients with severe malaria than in those with uncomplicated disease. The mean concentrations of both total IgG and IgG antiplasmodial antibodies tended to be highest in the group with uncomplicated disease while total IgE and IgE antibodies were higher in the group with severe disease. The IgE antibodies detected in approximately 65% of the patients were positively correlated to parasitemia. These results suggest that antiplasmodial IgG antibodies are involved in reducing the severity of P. falciparum malaria, while IgE antibodies may contribute to the pathogenesis of this infection.
Adolescent↗
Application of yeast enolase as antigen for immunodiagnosis of malaria.
In 1998, we reported that Plasmodium falciparum (Pf) enolase was useful as the capture antigen for the immunodiagnosis of malaria. In the present study, we modified a fluorescence-ELISA for the diagnosis of malaria by applying yeast enolase or rabbit muscle enolase as antigen. Sera from 67 falciparum malaria patients and 15 vivax malaria patients were tested by the method. Positivity rates of the former was 82.1% against yeast enolase antigen and 90.5% against rabbit muscle enolase antigen, and those of latter was 93.3% against both enolase antigens. Mean antibody level (RFU values) of sera from falciparum and vivax malaria patients were significantly higher than those from healthy individuals. There was a significant correlation between anti-yeast and anti-rabbit muscle enolase antibody level (RFU values) in the group of falciparum subjects (r = 0.401, p<0.001). A significant correlation between RFU values against yeast enolase antigen and indirect fluorescent antibody titers against crude Pf antigen in the same subjects was recognized (r = 0.518, p<0.001). Longitudinal changes of RFU values against yeast enolase for the following 4 weeks after admission were also examined for sera from falciparum malaria patients. Patients with more severe malaria showed increasing RFU values as the clinical courses progressed. However, in the mild cases, each RFU value stayed unchanged during the course. We concluded that yeast and rabbit muscle enolase could be appropriately used as antigen for the immunodiagnosis of malaria.
Animals↗
Identification of a Wnt-responsive signal transduction pathway in primary endothelial cells.
The beta-catenin signal transduction pathway, which can be activated by secreted Wnt proteins, plays a key role in normal embryonic development and in malignant transformation of the mammary gland and colon. Here we demonstrate, for the first time, that Wnt and beta-catenin signaling also function in cells of the vasculature. RT-PCR analysis showed that primary endothelial and smooth muscle cell cultures, of both mouse and human origin, express members of the Wnt and Wnt receptor (Frizzled) gene families. Transfection of an expression vector for Wnt-1 into primary endothelial cells increased both the free pool of beta-catenin and the transcription from a Lef/tcf-dependent reporter gene construct. Expression of Wnt-1, but not Wnt-5a, also stimulated proliferation of primary endothelial cell cultures. These data show that Wnt and Frizzled proteins can regulate signal transduction, via beta-catenin, in endothelial cells. These findings suggest that Wnt signaling may feature in normal differentiation of the vasculature as well as in pathological settings where endothelial and smooth muscle proliferation is disturbed.
Animals↗
Dietary lipid lowering reduces tissue factor expression in rabbit atheroma.
BACKGROUND: The mechanisms by which lipid lowering reduces the incidence of acute thrombotic complications of coronary atheroma in clinical trials remains unknown. Tissue factor (TF) overexpressed in atheroma may accelerate thrombus formation at the sites of plaque disruption. A cell surface cytokine CD40 ligand (CD40L) enhances TF expression in vitro. METHODS AND RESULTS: To test the hypothesis that lipid lowering reduces TF expression and activity, we produced atheroma in rabbit aortas by balloon injury and cholesterol feeding for 4 months (Baseline group, n=15), followed by either a chow diet (Low group, n=10) or a continued high-cholesterol diet for 16 months (High group, n=5). Immunolocalization of TF, CD40L, and its receptor CD40 was quantified by computer-assisted color image analysis. Macrophages in atheroma of the Baseline and High groups strongly expressed TF. Intimal smooth muscle cells and endothelial cells also contained immunoreactive TF. Regions of expression of CD40L and CD40 colocalized with TF. Protein expression of TF diminished substantially in the Low group in association with reduced expression of CD40L and CD40. In situ binding of TF to factors VIIa and X, detected by digoxigenin-labeled factors VIIa and X, colocalized with TF protein in atheroma and decreased after lipid lowering. We also determined reduced TF biological activity in the Low group by use of a chromogenic assay. The level of TF mRNA detected by reverse transcription-polymerase chain reaction also decreased after lipid lowering. CONCLUSIONS: These results suggest decreased expression and activity of TF as a novel mechanism of reduced incidence of thrombotic complications of atherosclerosis by lipid lowering.
Animals↗
BTEB2, a Krüppel-like transcription factor, regulates expression of the SMemb/Nonmuscle myosin heavy chain B (SMemb/NMHC-B) gene.
We have recently characterized the promoter region of the rabbit embryonic smooth muscle myosin heavy chain (SMemb/NMHC-B) gene and identified the 15-bp sequence, designated SE1, located at -105 from the transcriptional start site as an important regulatory element for its transcriptional activity in a smooth muscle cell (SMC) line. In this study, we attempted to isolate cDNA clones encoding for the transcription factors that control the expression of the SMemb gene through binding to this cis-regulatory element. We screened a lambdagt11 cDNA library prepared from C2/2 cells, a rabbit-derived SMC line, by using a radiolabeled concatenated oligonucleotide containing SE1 as a probe. Sequence analysis revealed that one of the cDNA clones corresponds to the rabbit homologue of basic transcriptional element binding protein-2 (BTEB2), which has previously been identified as one of the Krüppel-like transcription factor. Gel mobility shift assays and antibody supershift analyses with nuclear extracts from C2/2 cells indicate that BTEB2 is a major component of nuclear factor:SE1 complexes. Furthermore, a glutathione S-transferase-BTEB2 fusion protein binds to the SE1 in a sequence-specific manner. In support of the functionality of BTEB2 binding, basal promoter activity and BTEB2-induced transcriptional activation were markedly attenuated by the disruption of the SE1. In adult rabbit tissues, BTEB2 mRNA was most highly expressed in intestine, urinary bladder, and uterus. BTEB2 mRNA levels were downregulated in rabbit aorta during normal development. Moreover, immunohistochemical analysis indicated a marked induction of BTEB2 protein in the neointimal SMC after balloon injury in rat aorta. These results suggest that BTEB2 mediates the transcriptional regulation of the SMemb/NMHC-B gene and possibly plays a role in regulating gene expression during phenotypic modulation of vascular SMC.
Age Factors↗
Matrix metalloproteinase inhibition attenuates early left ventricular enlargement after experimental myocardial infarction in mice.
BACKGROUND: Extracellular matrix synthesis and degradation contribute to the morphological changes that occur after myocardial infarction (MI). METHODS AND RESULTS: We tested the hypothesis that inhibition of matrix metalloproteinases (MMPs) attenuates left ventricular remodeling in experimental MI. Seventy-one male FVB mice that survived ligation of the left anterior coronary artery were randomized to a broad-spectrum MMP inhibitor (CP-471,474) or placebo by gavage. Echocardiographic studies were performed before randomization (within 24 hours of surgery) and 4 days later and included short-axis imaging at the midpapillary and apical levels. Infarction as defined by wall motion abnormality was achieved in 79% of the procedures (n=56), and mortality rate during the 4-day protocol was 23% (9 of 36 on treatment vs 7 of 35 on placebo; P=NS). Baseline end-diastolic and end-systolic dimensions and areas were similar (P=NS) between treated and placebo groups. At follow-up, infarcted mice allocated to MMP inhibitor had significantly smaller increases in end-systolic and end-diastolic dimensions and areas at both midpapillary and apical levels compared with infarcted mice allocated to placebo (all P<0.05). In addition, infarcted animals that received MMP inhibitor had no change in fractional shortening (-3+/-13%), whereas animals that received placebo had a decrease in fractional shortening (-12+/-12%) (P<0.05). In an analysis stratified by baseline end-diastolic area, the effects of MMP inhibition on the changes in end-systolic area and end-diastolic area were most prominent in animals that had more initial left ventricular dilatation (both P<0.05). CONCLUSIONS: -Administration of an MMP inhibitor attenuates early left ventricular dilation after experimental MI in mice. Further studies in genetically altered mice and other models will improve understanding of the role of MMPs in left ventricular remodeling.
Animals↗
Plasmodium falciparum subtilisin-like protease 2, a merozoite candidate for the merozoite surface protein 1-42 maturase.
The process of human erythrocyte invasion by Plasmodium falciparum parasites involves a calcium-dependent serine protease with properties consistent with a subtilisin-like activity. This enzyme achieves the last crucial maturation step of merozoite surface protein 1 (MSP1) necessary for parasite entry into the host erythrocyte. In eukaryotic cells, such processing steps are performed by subtilisin-like maturases, known as proprotein convertases. In an attempt to characterize the MSP1 maturase, we have identified a gene that encodes a P. falciparum subtilisin-like protease (PfSUB2) whose deduced active site sequence resembles more bacterial subtilisins. Therefore, we propose that PfSUB2 belongs to a subclass of eukaryotic subtilisins different from proprotein convertases. Pfsub2 is expressed during merozoite differentiation and encodes an integral membrane protein localized in the merozoite dense granules, a secretory organelle whose contents are believed to participate in a late step of the erythrocyte invasion. PfSUB2's subcellular localization, together with its predicted enzymatic properties, leads us to propose that PfSUB2 could be responsible for the late MSP1 maturation step and thus is an attractive target for the development of new antimalarial drugs.
Amino Acid Sequence↗
Molecular cloning and nuclear localization of a histone deacetylase homologue in Plasmodium falciparum.
Reversible acetylation of core histones plays an important role in transcriptional regulation, cell cycle progression and developmental events. The acetylation state of histones is controlled by a dynamic equilibrium between activities of histone acetylase and deacetylase enzymes. Histone deacetylase (HDAC) was recently suggested to be the target of a fungus-derived antiprotozoal agent exhibiting structural similarity to known HDAC inhibitors. We have initiated a study of HDAC of human malaria parasite, Plasmodium falciparum, to evaluate its potential as the target for novel antimalarials and its role in parasite development. We have isolated HDAC1 gene from the P. falciparum genomic and cDNA libraries. The nucleotide sequence contains no intervening sequence and its open reading frame (ORF) codes for a protein of 449 amino acid residues. We have named the protein, PfHDAC1, as the sequence shows significant homology to yeast, human and other eukaryotic HDACs. Northern blot analysis of the total RNA from different asexual and sexual stages of the parasite reveals the presence of single mRNA transcript, which is predominantly expressed in mature asexual blood stages and in gametocytes. Antiserum raised against a carboxyl terminal peptide immunoprecipitated an in vitro translated P. falciparum HDAC gene product and recognized an approximately 50 kDa protein in the Triton X-100 insoluble fraction of parasites. Immunoelectron microscopy analysis showed majority of the protein localized in the nucleus of P. falciparum. To our knowledge, this is the first HDAC gene isolated from the malaria parasite.
Amino Acid Sequence↗
Plasmodium gallinaceum: a novel morphology of malaria ookinetes in the midgut of the mosquito vector.
Malaria ookinetes invade midgut epithelial cells of the mosquito vector from the bloodmeal in the lumen of the mosquito midgut, but the cellular interactions of ookinetes with the mosquito vector remain poorly described. We describe here a novel morphology of Plasmodium gallinaceum ookinetes in which the central portion of the ookinete is an elongated narrow tube or stalk joining the anterior and posterior portions of the parasite. We propose that the previously undescribed stalkform ookinete may be an adaptation to facilitate parasite locomotion through the cytoplasm of mosquito midgut epithelial cells.
Aedes↗
Morphological analysis of isolated rhoptries from Plasmodium yoelii, P. berghei, and P. chabaudi merozoites.
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Animals↗