Nonvascular role for VEGF: VEGFR-1, 2 activity is critical for neural retinal development.
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Angiogenesis Inhibitors↗
Biomedical subjects
X Xu
Publications and source records attributed to X Xu.
Modulation of renal oxygen consumption by nitric oxide is impaired after development of congestive heart failure in dogs.
We investigated the role of nitric oxide (NO) in the modulation of renal O2 consumption in dogs with pacing-induced congestive heart failure (CHF). O2 consumption in the renal cortex (C) and medulla (M) of normal dogs and dogs with CHF was measured under control conditions and in the presence of increasing concentrations of three stimulators of NO production, bradykinin, ramiprilat, and amlodipine, or the NO donor S-nitroso-N-acetylpenicillamine (SNAP). Baseline O2 consumption (nmol O2/min per gram) was similar in the CHF group (C: 637+/-65; M: 618+/-83) and the control group (C: 601+/-58, M: 534+/-55). In normal dogs, bradykinin (10(-4) M), ramiprilat (10(-4) M), amlodipine (10(-5) M) and SNAP (10(-4) M) all significantly reduced O2 consumption in the cortex (-31.5+/-3.5%, -33+/-2.5%, -28.4+/-4.9%, -49.3+/-3.1%) and medulla (-26.9+/-2.2%, -31.4+/-2.2%, -23.1+/-1.3%, -48.3+/-4%), respectively. The responses to bradykinin, ramiprilat and amlodipine were significantly attenuated in dogs with CHF (C: -22.2+/-1.8%, -20.1+/-2.6%, -14.2+/-2.5%; M: -20.8+/-1.7%, -17.8+/-1.9%, -15.6+/-2.6%, respectively; p < 0.05). The responses in dogs with CHF were not altered by NO synthase blockade with L-NAME (10(-4) M). In contrast, in normal kidneys treatment with L-NAME significantly attenuated the response to all three stimuli of NO production. Responses to SNAP were not affected either by CHF or L-NAME. These data indicate that the role of NO production in the modulation of tissue O2 consumption in the kidney is impaired after the development of pacing-induced heart failure in dogs.
Amlodipine↗
Restoration of normal ventricular electrophysiology in renovascular hypertensive rabbits after treatment with losartan.
Left ventricular hypertrophy (LVH) is associated with abnormal ventricular electrophysiology. We have shown complete regression of LVH and normalization of ventricular electrophysiology in renovascular hypertensive rabbits treated with captopril. To determine if angiotensin II type 1 receptor (AT1) blockade produces the same benefit, we treated hypertensive rabbits with losartan for 3 months. LVH was evaluated by heart-to-body weight ratio (HW/BW). Vulnerability to ventricular arrhythmia was assessed by ventricular fibrillation threshold (VFT) and dispersion of effective refractory period (ERP). The electrical properties of single left ventricular myocytes were characterized by action potential duration at 90% repolarization (APD90) and inward rectifier K+ current (I(K1)) density. Hypertensive rabbits treated with vehicle (LVH/Vehicle) had higher mean arterial pressure (MAP, 81+/-2 vs. 60+/-2 mm Hg) and HW/BW (2.71+/-0.07 vs. 1.97+/-0.04 g/kg), lower VFT (20+/-1 vs. 39+/-2 mA), larger dispersion of ERP (34+/-3 vs. 14+/-3 ms), longer APD90 (187+/-6 vs. 162+/-6 ms) and lower I(K1) density compared with control rabbits. Hypertensive rabbits treated with losartan (LVH/Losartan) had HW/BW (2.36+/-0.06 g/kg) between those of LVH/Vehicle and control rabbits, whereas MAP (65+/-2 mm Hg), VFT (34+/-2 mA), dispersion of ERP (19+/-1 ms), APD90 (160+/-6 ms), and I(K1) density were significantly different from LVH/Vehicle but similar to control. We conclude that AT1 blockade in renovascular hypertensive rabbits normalizes ventricular electrophysiology.
Action Potentials↗
Effects of exposure to organic solvents on menstrual cycle length.
To investigate the association between organic solvent exposure and menstrual disturbance, we conducted a cross-sectional study among 1408 petrochemical workers in China. Based on an industrial hygiene evaluation, we classified the workshops according to the presence or absence of organic solvents (benzene, styrene, toluene, or xylene). We used logistic regression to estimate odds ratios and 95% confidence intervals for prolonged menstrual cycle length (oligomenorrhea: average cycle length > 35 days during the previous year) associated with the exposure. After adjustment for confounders, each additional year of work in an exposed workshop was associated with a 7% increase in oligomenorrhea (odds ratio, 1.07; 95% confidence interval, 1.00 to 1.14). Compared with no exposure, 3 or more years of exposure was associated with a 53% increase in oligomenorrhea (odds ratio, 1.53; 95% confidence interval, 1.00 to 2.34). We concluded that exposure to organic solvents is associated with a trend toward increased frequency of oligomenorrhea.
Adult↗
Cloning and expression of two novel hemin binding protein genes from Treponema denticola.
Treponema denticola does not appear to produce siderophores, so it must acquire iron by other pathways. Indeed, T. denticola has been shown to have an iron-regulated 44-kDa outer membrane protein (HbpA) with hemin binding ability. To characterize the HbpA protein, its gene was cloned from genomic DNA libraries of T. denticola. Sequence analysis of the hbpA open reading frame indicated that it encoded a 42.8-kDa protein with a 23-amino-acid signal peptide. HbpA has no significant homology to any proteins in the databases. Southern blot analysis demonstrated that hbpA is present in several T. denticola ATCC strains and clinical isolates, but not in Treponema pectinovorum, Treponema socranskii, or Escherichia coli. HbpA, expressed as a recombinant protein in E. coli and purified by antibody affinity chromatography, has hemin binding activity as determined by lithium dodecyl sulfate-polyacrylamide gel electrophoresis with tetramethylbenzidine staining. Northern blot analysis showed that there were two hbpA-containing transcripts, of approximately 1.3 and 2.6 kb, and that the RNA levels were low-iron induced. Interestingly, the 2.6-kb mRNA also encoded a second protein with significant homology to hbpA. This downstream gene, called hbpB, was cloned and sequenced and its product was expressed as a fusion protein in E. coli. The hbpB gene product is 49% identical to HbpA and binds hemin. Thus, T. denticola has two novel hemin binding proteins which may be part of a previously unrecognized iron acquisition pathway.
Amino Acid Sequence↗
Role for hetC in the transition to a nondividing state during heterocyst differentiation in Anabaena sp.
Nitrogen-deprived filaments of wild-type or hetC Anabaena sp. produce respectively, at semiregular intervals, heterocysts and weakly fluorescent cells. Unlike heterocysts, the latter cells can divide and elongate, producing a pattern of spaced series of small cells. Because a hetR::gfp fusion is expressed most strongly in the small cells, we propose that these small cells represent a very early stage of heterocyst differentiation. hetC::gfp is expressed most strongly in proheterocysts and heterocysts.
ATP-Binding Cassette Transporters↗
Adenovirus DNA binding protein interacts with the SNF2-related CBP activator protein (SrCap) and inhibits SrCap-mediated transcription.
The SNF2-related CBP activator protein, SrCap (pronounced "sir cap"), shares homology with the SNF2/SWI2 protein family. SrCap was cloned through its ability to bind CBP. SrCap can function as a CBP coactivator and can activate transcription in a reporter assay when expressed as a Gal-SrCap fusion protein. A monoclonal antibody raised against the carboxyl terminus of SrCap coimmunoprecipitates CBP/p300, supporting the model that SrCap is a CBP binding protein and that these proteins can be found together in a cellular protein complex. In addition, several cellular proteins are coimmunoprecipitated by the SrCap-specific antibody. Since adenovirus E1A proteins interact with CBP/p300 proteins, we examined what proteins could be copurified in a SrCap-specific coimmunoprecipitation assay from lysates of adenovirus-infected cells. While E1A proteins were not detected in this complex, to our surprise, we observed the presence of an infected-cell-specific band of 72 kDa, which we suspected might be the adenovirus DNA binding protein, DBP. The adenovirus DBP is a multifunctional protein involved in several aspects of the adenovirus life cycle, including an ability to modulate transcription. The identity of DBP was confirmed by DBP-specific Western blot analysis and by reimmunoprecipitating DBP from denatured SrCap-specific protein complexes. Using in vitro-translated DBP and SrCap proteins, we demonstrated that these proteins interact. To determine whether this interaction could affect SrCap-mediated transcription, we tested whether increasing amounts of DBP could modulate the Gal-SrCap transcription activity. We observed that DBP inhibited Gal-SrCap transcription activity in a dose-dependent manner. These data suggest a novel mechanism of adenovirus host cell control by which DBP binds to and inactivates SrCap, a member of the SNF2 chromatin-remodeling protein family.
Adenosine Triphosphatases↗
Complete genome sequence of the shrimp white spot bacilliform virus.
We report the first complete genome sequence of a marine invertebrate virus. White spot bacilliform virus (WSBV; or white spot syndrome virus) is a major shrimp pathogen with a high mortality rate and a wide host range. Its double-stranded circular DNA genome of 305,107 bp contains 181 open reading frames (ORFs). Nine homologous regions containing 47 repeated minifragments that include direct repeats, atypical inverted repeat sequences, and imperfect palindromes were identified. This is the largest animal virus that has been completely sequenced. Although WSBV is morphologically similar to insect baculovirus, the two viruses are not detectably related at the amino acid level. Rather, some WSBV genes are more homologous to eukaryotic genes than viral genes. In fact, sequence analysis indicates that WSBV differs from all known viruses, although a few genes display a weak homology to herpesvirus genes. Most of the ORFs encode proteins that bear no homology to any known proteins, either suggesting that WSBV represents a novel class of viruses or perhaps implying a significant evolutionary distance between marine and terrestrial viruses. The most unique feature of WSBV is the presence of an intact collagen gene, a gene encoding an extracellular matrix protein of animal cells that has never been found in any viruses. Determination of the genome of WSBV will facilitate a better understanding of the molecular mechanism underlying the pathogenesis of the WSBV virus and will also provide useful information concerning the evolution and divergence of marine and terrestrial animal viruses at the molecular level.
Amino Acid Sequence↗
cis-Acting signals in encapsidation of Hantaan virus S-segment viral genomic RNA by its N protein.
The nucleocapsid (N) protein encapsidates both viral genomic RNA (vRNA) and the antigenomic RNA (cRNA), but not viral mRNA. Previous work has shown that the N protein has preference for vRNA, and this suggested the possibility of a cis-acting signal that could be used to initiate encapsidation for the S segment. To map the cis-acting determinants, several deletion RNA derivatives and synthetic oligoribonucleotides were constructed from the S segment of the Hantaan virus (HTNV) vRNA. N protein-RNA interactions were examined by UV cross-linking studies, filter-binding assays, and gel electrophoresis mobility shift assays to define the ability of each to bind HTNV N protein. The 5' end of the S-segment vRNA was observed to be necessary and sufficient for the binding reaction. Modeling of the 5' end of the vRNA revealed a possible stem-loop structure (SL) with a large single-stranded loop. We suggest that a specific interaction occurs between the N protein and sequences within this region to initiate encapsidation of the vRNAs.
Base Sequence↗
Abnormal calcium and protein kinase C-epsilon signaling in hypertrophied atrial tumor myocytes (AT-1 cells).
Cardiac hypertrophy leads to contractile dysfunction and altered hormone responsiveness through incompletely understood mechanisms. Atrial tumor (AT-1) myocytes (AT-1 cells) are a cardiomyocyte lineage that proliferates but hypertrophies when proliferation is prevented with mitomycin C. Because both states maintain a highly differentiated phenotype, AT-1 cells were used to explore the signaling pathways that accompany and/or contribute to hypertrophic cardiomyocyte growth. Mitomycin C-induced AT-1 cell enlargement is associated with a pronounced increase in the amplitude and the duration of both electrically stimulated calcium transients and endothelin receptor-dependent calcium responses. Studies with caffeine indicate that the intracellular pool of releasable calcium is similar in control and hypertrophied AT-1 cells. This agrees with the results of Northern analyses that show similar steady-state levels of transcripts encoding the sarcoplasmic reticulum Ca-ATPase (and higher levels of transcripts encoding the Na+/Ca2+ exchanger) in hypertrophied AT-1 cells, relative to proliferating control cultures. However, immunoblot analyses reveal a marked increase in the expression of protein kinase C (PKC)-epsilon (a critical intermediate in the signaling pathway for endothelin receptor-dependent modulation of intracellular calcium) during AT-1 cell hypertrophy; the abundance of other PKC isoforms is not changed. Collectively, these results identify reciprocal regulation between calcium/PKC signaling and hypertrophic growth. The evidence that AT-1 cell hypertrophy leads to abnormalities in calcium regulation and specific changes in PKC-epsilon expression that alter endothelin receptor responsiveness supports the notion that pathophysiological changes in PKC-epsilon abundance lead to functionally important changes in hormonal modulation of cardiomyocyte function.
Animals↗
Ventricular hypertrophy amplifies transmural repolarization dispersion and induces early afterdepolarization.
The effects of left ventricular hypertrophy (LVH) on the generation of phase 2 early afterdepolarization (EAD) and transmural dispersion of repolarization (TDR) were assessed using arterially perfused rabbit ventricular wedge preparations. Transmembrane action potentials from epicardium, subendocardium, and endocardium were simultaneously recorded together with a transmural ECG. Transmural action potential duration (APD) was also mapped. LVH (renovascular hypertension model) produced significant prolongation in ventricular APD and QT interval. Preferential APD prolongation in subendocardium and endocardium was associated with a marked increase in TDR. Phase 2 EADs were generated from subendocardium or endocardium in all LVH rabbits (15 of 15) in the absence of APD prolonging agents at basic cycle lengths of 2,000-4,000 ms. Phase 2 EAD could produce "R on T" extrasystoles, initiating polymorphic ventricular tachycardia (VT). This study provides the first direct evidence from intracellular recordings that phase 2 EAD could be generated from rabbit intact hypertrophied LV wall in the absence of APD prolonging agents, resulting in R on T extrasystoles capable of initiating polymorphic VT under enhanced TDR.
Action Potentials↗
Endothelial nitric oxide synthase plays an essential role in regulation of renal oxygen consumption by NO.
Nitric oxide (NO) regulates renal O2 consumption, but the source of NO mediating this effect is unclear. We explored the effects of renal NO production on O2 consumption using renal cortex from mice deficient (-/-) in endothelial (e) nitric oxide synthase (NOS). O2 consumption was determined polarographically in slices of cortex from control and eNOS-/- mice. NO production was stimulated by bradykinin (BK) or ramiprilat (Ram) in the presence or absence of an NOS inhibitor. Basal O2 consumption was higher in eNOS-/- mice than in heterozygous controls (919 +/- 46 vs. 1,211 +/- 133 nmol O(2). min(-1). g(-1); P < 0.05). BK and Ram decreased O2 consumption significantly less in eNOS-/- mice [eNOS-/-: BK -19.0 +/- 2.8%, Ram -20.5 +/- 3.3% at 10(-4) M; control: BK -29.5 +/- 2.5%, Ram -34 +/- 1.6% at 10(-4) M]. The NO synthesis inhibitor nitro-L-arginine methyl ester (L-NAME) attenuated this decrease in control but not eNOS-/- mice. An NO donor inhibited O2 consumption similarly in both groups independent of the presence of L-NAME. These results demonstrate that NO production by eNOS is responsible for regulation of renal O2 consumption in mouse kidney.
Angiotensin-Converting Enzyme Inhibitors↗
Simvastatin reverses impaired regulation of renal oxygen consumption in congestive heart failure.
Nitric oxide (NO) production by endothelial nitric oxide synthase (eNOS) regulates renal O(2) consumption. This mechanism is impaired in heart and kidney of dogs with heart failure (CHF). Simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, increases eNOS expression in the endothelium. Therefore, we studied whether simvastatin treatment could restore the regulation of renal O(2) consumption by stimulators of NO production in dogs with CHF. Renal O(2) consumption was measured after stimulation of NO production with bradykinin, ramiprilat, or amlodipine or the NO donor S-nitroso-N-acetylpenicillamine (SNAP). Simvastatin delayed the time to euthanasia in dogs with CHF (35 +/- 1.0 vs. 29 +/- 1.2 days; P < 0.01). In normal dogs, bradykinin (10(-4) M), ramiprilat (10(-4) M), amlodipine (10(-5) M), and SNAP (10(-4) M) significantly reduced O(2) consumption in the renal cortex (-31.8 +/- 0.9, -30.3 +/- 1.1, -30.1 +/- 2.0, -46.9 +/- 1.0%) and renal medulla (-29.7 +/- 2.1, -33.0 +/- 2.7, -30.8 +/- 2.2, -46.8 +/- 1.1%). Responses to bradykinin, ramiprilat, and amlodipine were significantly attenuated in CHF but were partially or completely restored by simvastatin. Responses to SNAP were unaffected. These data demonstrate that treatment with simvastatin improves renal production of NO in CHF, restoring the normal regulation of renal O(2) consumption by NO.
Amlodipine↗
Progesterone, but not medroxyprogesterone, inhibits vascular cell adhesion molecule-1 expression in human vascular endothelial cells.
-It has been shown that ovarian steroid hormones can reduce the incidence of cardiovascular disease in postmenopausal women. As hormone replacement therapy for postmenopausal women, progestins are added to estrogens to eliminate the increased risk of endometrial cancer. However, the effects of progestins on the atherogenic process have not been well understood. In the present study, we examined the effects of progestins on the expression of vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vein endothelial cells (HUVECs). Immunocytochemical analysis revealed the presence of progesterone receptors in HUVECs. Progesterone clearly inhibited tumor necrosis factor-alpha-activated expression of VCAM-1 protein and its mRNA in HUVECs. Synthetic progesterone receptor agonist R5020 also inhibited the tumor necrosis factor-alpha-activated VCAM-1 expression, whereas medroxyprogesterone acetate (MPA) failed to do so. Electrophoretic mobility shift assays demonstrated that progesterone, but not MPA, inhibited DNA binding of the transcription nuclear factor-kappaB, which is critical for the inducible expression of VCAM-1. Because the expression of VCAM-1 is one of the earliest events that occurs in the atherogenic process, this adhesion molecule might be a target molecule for progesterone on vascular walls. The contrasting effects of progesterone and MPA seem clinically important, inasmuch as MPA is a widely used progestin in the regimen of hormone replacement therapy.
Endothelium, Vascular↗
Asthma, rhinitis, and skin test reactivity to aeroallergens in families of asthmatic subjects in Anqing, China.
In industrialized countries with a Western lifestyle, sensitization to perennial aeroallergens is strongly associated with asthma, whereas sensitization to seasonal aeroallergens is closely related to allergic rhinitis. Little is known, however, about the relation between skin test reactivity to aeroallergens and either asthma or rhinitis in mainland China. We studied 10,009 members of 2,544 families in Anqing (China) that were selected on the basis of physician-diagnosed asthma in at least two siblings. Generalized estimating equations were employed to study the association between skin test reactivity to aeroallergens and either asthma or rhinitis. After adjustment for age, sex, intensity of smoking, skin test reactivity to other aeroallergens, and household correlations, sensitization to dust mite was an independent predictor of both asthma (OR = 1.3, 95% CI = 1.1 to 1.5, p = 0.008) and rhinitis (OR = 1.3, 95% CI = 1.0 to 1.8, p = 0.04). Sensitization to mold was significantly associated with asthma (OR = 1.6, 95% CI = 1.1 to 2.3, p = 0.008), and sensitization to silk was an independent predictor of rhinitis (OR = 1.5, 95% CI = 1.1 to 2.2, p = 0.02). Although 46.9% of the study participants were sensitized to at least one allergen, only 3.5% of study subjects reported nasal symptoms consistent with rhinitis. Among asthmatic subjects, 6.2% reported nasal symptoms. Whereas sensitization to perennial aeroallergens was associated with asthma among families of asthmatic subjects in rural China, sensitization to silk was the strongest predictor of rhinitis in this population. Our findings also suggest that allergic rhinitis is far less common among asthmatic subjects in rural China than in asthmatic subjects in industrialized countries with a Western lifestyle.
Adolescent↗
Association of asthma with beta(2)-adrenergic receptor gene polymorphism and cigarette smoking.
Recent studies have suggested that two polymorphisms of the beta(2)-adrenergic receptor (beta(2)AR) gene at codons 16 (arginine to glycine) and 27 (glutamine to glutamate) affect an individual's airway responsiveness, or response to acute or chronic beta(2)-agonist therapy but are not risk factors for asthma. We hypothesize that there is an interaction effect on asthma between the beta(2)AR gene polymorphisms and cigarette smoking. A case-control study was conducted in 128 asthma cases and 136 control individuals identified from 10,014 studied subjects in rural Anqing, China. Allele-specific polymerase chain reaction (PCR) was used to genotype beta(2)AR gene polymorphisms. Multiple logistic regression was used to adjust for potential confounding factors. We found a marginally significant interaction between cigarette smoking and beta(2)AR-16 genotype after adjusting for important confounding factors (p = 0.06). Specifically, we found that compared with never-smoking Gly-16 homozygotes, those ever-smokers who are Arg-16 homozygotes had a significantly increased risk of asthma (odds ratio [OR] = 7.81; 95% confidence interval [CI]: 2.07 to 29.5). This association showed a clear dose-response relationship with the number of cigarettes smoked. However, there was no significant association of asthma with polymorphisms of the beta(2)AR at position 27 (OR = 1.38; 95% CI: 0.69 to 2.73). Our study suggests a gene-environment interaction between the Arg-16 genotype and ever cigarette smoking with respect to the susceptibility of an individual to asthma.
Adult↗
PPARalpha and GR differentially down-regulate the expression of nuclear factor-kappaB-responsive genes in vascular endothelial cells.
The antiinflammatory action of glucocorticoids is mediated partly by the inhibition of the expression of several cytokines and adhesion molecules. Some activators for nuclear receptors other than the GR have also been shown to inhibit the expression of these inflammatory molecules, although their molecular mechanisms remain unidentified. We therefore examined the effects of the PPARalpha activator fenofibrate and the GR activator dexamethasone on TNFalpha-stimulated expression of IL-6 and vascular cell adhesion molecule-1 in vascular endothelial cells. Both fenofibrate and dexamethasone reduced TNFalpha-induced IL-6 production in human vascular endothelial cells, but only fenofibrate reduced TNFalpha-stimulated vascular cell adhesion molecule-1 expression in these cells. Transient transfection of bovine aortic endothelial cells with an IL-6 promoter construct or a vascular cell adhesion molecule-1 promoter construct revealed that fenofibrate inhibited TNFalpha-induced IL-6 promoter as well as vascular cell adhesion molecule-1 promoter activities, whereas dexamethasone inhibited only the former. EMSA demonstrated that both fenofibrate and dexamethasone reduced nuclear factor-kappaB binding to its recognition site on the IL-6 promoter, but only fenofibrate reduced such binding to the vascular cell adhesion molecule-1 promoter. Thus, down-regulation of nuclear factor-kappaB activity by PPARalpha occurs in both the IL-6 and vascular cell adhesion molecule-1 genes, whereas that by GR occurs only in the IL-6 gene in vascular endothelial cells. These results strongly suggest the existence of a target gene-specific mechanism for the nuclear receptor-mediated down-regulation of nuclear factor-kappaB activity.
Biological Transport↗
Salt-stress-responsive membrane proteins in Rhodobacter sphaeroides f. sp. denitrificans IL 106.
The salt-mediated-stress response in Rhodobacter sphaeroides f. sp. denitrificans IL 106 was investigated by culturing cells in the presence and in the absence of NaCl in growth media. Fractionation of cells followed by SDS-PAGE and 2D-PAGE revealed an increase in the levels of membrane proteins of 39 and 50 kDa and a decrease in the level of a membrane protein of 52 kDa with increasing levels of external NaCl. The proteins were isolated and sequenced. The polypeptide of 50 kDa in the inner membrane was assigned to an ATP synthase beta chain and that of 52 kDa in the outer membrane to a flagellar filament protein. As the N terminal of the 39 kDa protein in the outer membrane was blocked, partial proteolysis was carried out and four peptides were sequenced. Each sequence exhibited no significant homology with those available in databases, suggesting that the polypeptide of 39 kDa (named SspA) is a novel salt-stress-induced protein.
Journal Article↗