Biomedical subjects

Xuejun Wang

Publications and source records attributed to Xuejun Wang.

31 records · Page 2Linked to original sources

PubMed2005

Remodeling of gap junctions and slow conduction in a mouse model of desmin-related cardiomyopathy.

OBJECTIVE: We studied a transgenic mouse model of human desmin-related cardiomyopathy with cardiac-specific expression of a 7-amino acid deletion mutation in desmin (D7-des) to test the hypothesis that impaired linkage between desmin and desmosomes alters expression and function of the electrical coupling protein, connexin43 (Cx43). METHODS: Expression of Cx43 and selected mechanical junctions proteins was characterized in left ventrices of D7-des and control mice by quantitative confocal microscopy and immunoblotting. Remodeling of gap junctions was also analyzed by electron microscopic morphometry. The electrophysiological phentoype of D7-des mice was characterized by electrocardiography and optical mapping of transmembrane voltage. RESULTS: Cx43 signal at intercalated disks was decreased by approximately 3-fold in D7-des ventricular tissue due to reductions in both gap junction number and size. Immunoreactive signal at cell-cell junctions was also reduced significantly for adhesion molecules and linker proteins of desmosomes and fascia adherens junctions. Electron microscopy showed decreased gap junction remodeling. However, immunoblotting showed that the total tissue content of Cx43 and mechanical junction proteins was not reduced, suggesting that diminished signal at cell-cell junctions was not due to insufficient protein expression, but to failure of these proteins to assemble properly within electrical and mechanical junctions. Remodeling of gap junctions in D7-des mice led to slowing of ventricular conduction as demonstrated by optical electrophysiological mapping. CONCLUSIONS: These results illustrate how a defect in a protein conventionally thought to fulfill a mechanical function in the heart can also lead to electrophysiological alterations that may contribute to arrhythmogenesis.

Animals↗

PubMed2005

Myocardial expression and redistribution of GRKs in hypertensive hypertrophy and failure.

G-protein-coupled receptor kinases (GRKs) are involved in cardiac hypertrophy and failure. But their temporal expression and cellular localization during the development of hypertrophy and its transition to failure remains to be investigated. In this study, we determined the expression and subcellular distribution of GRK2, GRK3, GRK5, and GRK6 in cardiac myocytes of 2- to 24-month-old spontaneously hypertensive heart failure (SHHF) rats. GRK2 increased in the intercalated disks in 6-, 12-, and 24-month-old SHHF rats, although total expression remained relatively constant from 2 to 24 months in both SHHF and normotensive rats. GRK3 expression progressively increased in 6-, 12-, and 24-month-old SHHF rats and was significantly higher than in age-matched controls. Immunolabeling of GRK3 showed a typical pattern of cross-striations that colocalized with alpha-actinin and G(alphas) at Z-lines in both SHHF and control rats. GRK5 expression showed no change from 2 to 24 months in both SHHF and normotensive rats. Confocal analysis revealed nuclear translocation of GRK5 in myocytes of SHHF rats. GRK6 had a striated pattern colocalized with alpha-actinin at Z-lines in the cytoplasm and was also present in the intercalated disks of cardiac myocytes from both SHHF and control rats. GRK6 expression increased in 12- and 24-month-old SHHF rats and was significantly higher than in age-matched controls. GRK6 labeling was reduced at the intercalated disks, but increased in the cytoplasm of cardiac myocytes from SHHF rats compared to age-matched controls. The increased expression of GRK3 and GRK6 and subcellular redistribution of GRK2, GRK5, and GRK6 in SHHF rats may be involved in abnormal remodeling of cardiac myocytes in hypertensive hypertrophy and failure.

Animals↗

PubMed2004

Modeling and simulation of point-non-point source effluent trading in Taihu Lake area: perspective of non-point sources control in China.

The past decades have witnessed some efforts in point source water pollution controls in China. However, adequate abatement efforts have not been implemented on non-point source control, and non-point source contributions remain and have increased as a share of surface water degradation. It has been noted that conventional command-and-control regulations are ineffective for agricultural non-point source pollution, and watershed abatement trading between point and non-point sources may serve as a cost-effective way to deal with it. In this paper, the feasibility of point-non-point sources effluent trading in China and cost-effectiveness of the trading system on water pollution control are evaluated using a stochastic programming model and a combined probabilistic watershed simulation of a representative agricultural watershed in the Taihu Lake area. The method and model can be used to assess economic and environmental opportunities of trading in similar watersheds in China. The use of explicit emission target and reliability decision rules in the chance-constrained programming model is a practical simplification to convert a stochastic program into a solvable deterministic problem. Based on the simulation, suggestions on development and implementation of point-non-point sources abatement trading scheme in China were discussed.

Agriculture↗

PubMed2004

Anisotropic in-plane gradients of poly(acrylic acid) formed by electropolymerization with spatiotemporal control of the electrochemical potential.

Laterally varying thickness gradients of poly(acrylic acid) (PAA) were formed by Zn(II)-catalyzed electropolymerization of acrylic acid (AA) in the presence of an in-plane electrochemical potential gradient applied to Au working electrodes. In the static potential gradient (SPG) approach, two ends of a Au working electrode were clamped at distinct potentials for the duration of the electropolymerization process, thereby generating a time-independent in-plane electrochemical potential gradient, V(x). A dynamic potential gradient (DPG) approach was also used, in which the two end potentials were varied in time, while maintaining a constant voltage offset, to generate an in-plane electrochemical potential gradient, V(x,t). Because the kinetics of heterogeneous electron transfer vary with the local overpotential, these two methods produce PAA films with laterally varying thickness gradients, although they exhibit different spatial characteristics. X-ray photoelectron spectroscopy (XPS) and surface plasmon resonance (SPR) imaging were used to characterize the PAA gradients. The in-plane thickness variations of PAA gradients formed by both SPG and DPG approaches agree with predictions of the Butler-Volmer equation at small absolute overpotentials, while at large (negative) overpotentials, mass transport dominates, and the thickness reaches a plateau value independent of local potential. DPG-produced PAA gradients are generally broader than SPG gradients with the same initial potential and comparable effective growth time, indicating that the DPG approach is more suitable for formation of thicker gradients.

Journal Article↗

PubMed2004

In situ dynamically monitoring the proteolytic function of the ubiquitin-proteasome system in cultured cardiac myocytes.

The ubiquitin-proteasome system (UPS) is responsible for turnover of most cellular proteins in eukaryotes. Protein degradation by the UPS serves quality control and regulatory functions. Proteasome inhibition showed great promise in effectively treating cancer and restenosis. UPS dysfunction in cardiac hypertrophy and failure has recently been suspected but remains to be investigated. A system capable of monitoring dynamic changes in proteolytic function of the UPS in cardiac myocytes in situ would no doubt benefit significantly efforts to decipher the pathogenic significance of UPS dysfunction in the heart and to evaluate the effect of proteasome inhibition on cardiac myocytes. We successfully established such a system in cultured cardiac myocytes by delivering and expressing a modified green fluorescence protein (GFPu) gene using recombinant adenoviruses. GFPu contains a ubiquitination signal sequence fused to the COOH terminus. Fluorescence microscopy and Western blots revealed that protein abundance of modified green fluorescent protein (GFPu), but not wild-type green fluorescent protein, in cultured cardiac myocytes was incrementally increased when function of the proteasomes was inhibited in various degrees by specific inhibitors. The increase in GFPu protein levels and fluorescence intensity is paralleled by a decrease in the in vitro peptidase activity of the proteasomes. Our results demonstrate that GFPu can be used as a surrogate marker to monitor dynamic changes in proteolytic function of the UPS in cardiac myocytes in situ. Application of this novel system reveals that moderate levels of H2O2, a reactive oxygen species generator, impair proteolytic function of the UPS in cultured cardiac myocytes.

Adenoviridae↗

PubMed2004

Multimedia fate model for hexachlorocyclohexane in Tianjin, China.

A level III fugacity model was applied to characterize the fate of gamma-HCH in Tianjin, China, before the 1990s when the contamination reached its maximum at steady state. Geometric means were used as model inputs. The concentrations of gamma-HCH in air, surface water, soil, sediment, crops, and fish as well as transfer fluxes across the interface between the compartments were derived under the assumption of steady state. The calculated concentrations were validated by independent data collected from the literature. There was generally good agreement between the estimated and the observed concentrations, and the differences were all less than 0.6 log units for air, water, soil, sediment, and fish and approximately 1 order of magnitude for crops. Around 97% of gamma-HCH accumulated in soil and sediment. Wastewater irrigation was not an important pathway for delivering gamma-HCH to soil as compared to the dominant source of agricultural application. Degradation and advective airflow carried much gamma-HCH out of the system. Sensitivities of the model estimates to input parameters were tested, and a coefficient of variation normalized sensitivity coefficient was defined for the test. The most influential parameters were degradation rates in sediment and soil, application rates, concentrations in wastewater, and adsorption coefficients. Monte Carlo simulation was conducted for model uncertainty analysis. The model was run 20 000 times using randomly generated data from predefined log-normal distribution density functions. All calculated concentrations and fluxes were log-normally distributed. The dispersions of the calculated and observed concentrations were compared in terms of coefficients of variation to distinguish between true variability and model uncertainty.

Air↗

PubMed2004

Genetic modification of the heart: chaperones and the cytoskeleton.

In the past decade, genetic modification has been extensively employed to define (patho)physiological roles of chaperones and the cytoskeleton in the heart, promoting dramatic advances in this field. Both loss-of-function and gain-of-function approaches have been used productively. alphaB-Crystallin (CryAB) is the most abundant small heat shock protein (HSP) in the heart. A missense mutation (R120G) in CryAB that is linked to human desmin-related myopathy (DRM), has proved in transgenic (TG) mice to be causative, likely through compromising the function of both CryAB and desmin filaments and inducing aberrant protein aggregation. For the molecular chaperones, the consensus gained is that up-regulation of each of the HSPs in the heart is protective against insults such as ischemia/reperfusion (I/R) injury. CryAB modulates protein aggregation of abnormal desmin. With respect to the cytoskeleton, disruption of the non-sarcomeric actin linkage at the intercalated discs via overexpressing the VASP-EHV1 domain is sufficient to cause dilated cardiomyopathy (DCM). Up-regulation of microtubule-associated protein 4 (MAP4) results in microtubule densification. Myocyte contractile malfunction characteristic of pressure overload hypertrophy is recapitulated by cardiac-restricted overexpression of MAP4. In contrast, overexpression of desmin filaments by itself is not detrimental to the heart. Although loss-of-function studies have been more limited, ablation of the desmin gene causes mitochondrial dysfunction and apoptosis, resulting in cardiomyopathy in mice. From function studies, abnormal desmin aggregation and disruption of the desmin networks resulting from expression of either mutant desmin or mutant CryAB have been shown to remodel the heart and compromise cardiac function, suggesting their synergistic roles in disease pathogenesis.

Actin Cytoskeleton↗

PubMed2003

AlphaB-crystallin modulates protein aggregation of abnormal desmin.

AlphaB-crystallin (CryAB) is the most abundant small heat shock protein in the heart. Upregulation of CryAB in desmin-related myopathy and its downregulation in end-stage congestive heart failure have both been reported. We previously demonstrated via cardiac-specific transgenesis that modest increases in normal CryAB are not detrimental to the heart, whereas expression of the R120G mutation of CryAB caused a desminopathy. It is generally believed that CryAB plays an important role in protecting the intermediate filaments, but the underlying mechanism is unclear. We hypothesized that CryAB protects the desmin filaments via preventing abnormal desmin protein from aggregating adversely. To test this hypothesis in vivo, mice expressing a desmin mutation that causes a desmin-related cardiomyopathy (D7) were bred into the R120G-CryAB transgenic (TG) background to examine the accumulation and aberrant aggregation of desmin protein. Despite lower mRNA expression of D7-des than in the D7-des TG hearts, the double-TG myocardium exhibited significantly higher desmin protein levels and dramatically more aberrant desmin aggregates than the D7-des TG hearts. The double-TG mice displayed a significantly stronger cardiac hypertrophic response, with the mice dying of congestive heart failure before 7 weeks. To explore the ability of wild-type (WT) CryAB to protect against mutant desmin, a desmin mutant was expressed in both the conventional and WT-CryAB stably transfected HEK cells. Significantly less aberrant desmin aggregation was observed in the WT-CryAB-overexpressing cells than in the HEK cells. The results suggest that CryAB modulates abnormal desmin aggregation and can serve a cardioprotective role.

Animals↗

PubMed2003

Fate modeling of phenanthrene with regional variation in Tianjin, China.

A multimedia fate model with spatially resolved air and soil phases was developed and evaluated. The model was used for calculation of phenanthrene concentrations in air, water, soil, and sediment in Tianjin area and transport fluxes between the adjacent bulk phases under steady-state assumption. Both air and soil phases were divided into 3113 individual compartments of 4 km2 each to assess the spatial variation of phenanthrene concentrations and fluxes. Independently measured phenanthrene concentrations in air, water, and soil were used for model validation. The spatial variation in soil was validated using a set of measured phenanthrene concentrations of 188 surface soil samples collected from the area. Most data used either for model calculation or for model validation were collected during the last 5 years. As the results of the model validation, the calculated mean values for phenanthrene concentrations in various bulk phases are in fair agreement with those independently observed and are very close to those calculated using the model without spatial variation. The absolute difference between the calculated and the measured mean concentrations are 0.14, 0.48, and 0.13 log-units (mol/m3) for air, water, and soil, respectively. The spatial distribution patterns of phenanthrene in both air and soil were well modeled. Spatially, however, the model overestimated the soil phenanthrene level at low concentration range and underestimated it at high concentration range. The calculated distribution of phenanthrene in the air matches well with the emission from fossil fuel combustion, while the calculated distribution pattern in the soil is similar to that observed.

China↗

PubMed2003

Subcellular redistribution of focal adhesion kinase and its related nonkinase in hypertrophic myocardium.

Focal adhesion kinase (FAK) and focal adhesion kinase-related nonkinase (FRNK) are likely involved in mechanical signaling during hypertension. We investigated expression, subcellular distribution, and phosphorylation of FAK, as well as FRNK in left ventricles of spontaneously hypertensive heart failure rats. Compared with normotensive controls, FAK and FRNK increased in left ventricles of hypertensive rats. Increased FAK and FRNK were mainly present in membrane cytoskeleton and nuclear fractions. Confocal microscopy demonstrated that FAK and FRNK translocated to nuclei and intercalated disks in cardiac myocytes from hypertensive rats. Serine and tyrosine phosphorylation of FAK increased dramatically in hypertensive rats. FAK phosphorylated at tyrosine 397 was present in membranes and intercalated disks, but not in nuclei. FAK was also phosphorylated on serine 722 but not on serine 910. In contrast, FRNK was phosphorylated on serine 217, the equivalent site of FAK serine 910, but not serine on 30, the homologous site of FAK serine 722. Serine phosphorylated FAK and FRNK accumulated in membranes and nuclei but not in intercalated disks. Nuclear translocation of FAK and FRNK may play important roles in regulating mechanical signal transduction in cardiac myocytes.

Active Transport, Cell Nucleus↗

PubMed2002

Desmin filaments and cardiac disease: establishing causality.

BACKGROUND: Gene targeting studies indicate that desmin is not required for embryonic myogenesis and heart formation but is essential for maintaining the structural and functional integrity of myocytes. Desmin-null mouse hearts developed hypertrophy and dilatation. However, the expression of desmin is very often upregulated rather than downregulated in many cardiac diseases. Altered distribution of desmin protein has been observed in dilated cardiomyopathy, as well as desminopathies to which a number of mutations of desmin and a missense mutation of alphaB-crystallin (CryAB) have been linked. METHODS AND RESULTS: Using mouse transgenesis, we have recently demonstrated that modest overexpression of a mutant form of either desmin or CryAB in the heart leads to aberrant aggregation of desmin and CryAB proteins, disruption of the normal desmin network, perturbation of myofibril alignment, and distortion of the nuclear shape. The transgenic hearts develop concentric cardiac hypertrophy and diastolic malfunction at the early stage and ventricular dilatation and congestive heart failure subsequently. Moderate overexpression of either wild-type protein, however, did not cause discernible morphological and functional abnormalities or increased mortality. CONCLUSIONS: Thus cardiac overexpression of wild-type desmin is not detrimental whereas aberrant aggregation of desmin and disruption of the desmin network remodel the heart and compromise cardiac function.

Animals↗

PubMed2002

[Application of turning band method in conditional simulation of soil heavy metals].

Geostatistical simulation techniques are widely used in studying spatial phenomena. The purpose of this study is to make an experimental study in applying this technique to understand the spatial distribution of copper and lead in wastewater irrigated agricultural soil in the eastern suburb of Beijing. The results showed that the simulation is efficient, because it fits to the main characteristics of the revealed reality of the spatial distribution of these elements. Geostatistical simulation could play an important role in regional environmental and ecological studies.

Copper↗

PubMedDate not supplied

Structural basis of ventricular remodeling: role of the myocyte.

Structural remodeling plays a major role in the progression of various heart diseases to congestive heart failure (CHF). Major contributors to this remodeling process in the heart include alterations in myocyte shape, myocyte number, and extracellular matrix. However, it is unclear as to which of these changes is most critical in the development of CHF, and this may vary by etiology. Myocyte shape alterations largely underlie the increase in chamber diameter/wall thickness characteristic of CHF. This review mainly focuses on the role of myocyte shape in ventricular remodeling. Several signaling molecules have been implicated in this process. As we learn more about the components of myocardial remodeling, new strategies to combat the progression of heart disease should arise.

Disease Progression↗