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Articles by X Yin
Total Records ( 8 ) for X Yin
  V. K Khor , R Dhir , X Yin , R. S Ahima and W. C. Song
 

Estrogen regulates fat mass and distribution and glucose metabolism. We have previously found that estrogen sulfotransferase (EST), which inactivates estrogen through sulfoconjugation, was highly expressed in adipose tissue of male mice and induced by testosterone in female mice. To determine whether inhibition of estrogen in female adipose tissue affects adipose mass and metabolism, we generated transgenic mice expressing EST via the aP2 promoter. As expected, EST expression was increased in adipose tissue as well as macrophages. Parametrial and subcutaneous inguinal adipose mass and adipocyte size were significantly reduced in EST transgenic mice, but there was no change in retroperitoneal or brown adipose tissue. EST overexpression decreased the differentiation of primary adipocytes, and this was associated with reductions in the expression of peroxisome proliferator-activated receptor-, fatty acid synthase, hormone-sensitive lipase, lipoprotein lipase, and leptin. Serum leptin levels were significantly lower in EST transgenic mice, whereas total and high-molecular-weight adiponectin levels were not different in transgenic and wild-type mice. Glucose uptake was blunted in parametrial adipose tissue during hyperinsulinemic-euglycemic clamp in EST transgenic mice. In contrast, hepatic insulin sensitivity was improved but muscle insulin sensitivity did not change in EST transgenic mice. These results reveal novel effects of EST on adipose tissue and glucose homeostasis in female mice.

  M Varella Garcia , A. P Schulte , H. J Wolf , W. J Feser , C Zeng , S Braudrick , X Yin , F. R Hirsch , T. C Kennedy , R. L Keith , A. E Baron , S. A Belinsky , Y. E Miller , T Byers and W. A. Franklin
 

Lung cancer usually is disseminated (advanced) and has a poor prognosis at diagnosis. Current and former smokers are at a high risk for lung cancer and are candidates for prevention and early detection strategies. Sputum is a potential source of biomarkers that might determine either lung cancer risk or the presence of early lung cancer, but no current sputum test is sufficiently sensitive and specific for effective screening. We used fluorescence in situ hybridization (FISH) to measure chromosomal aneusomy (CA) in sputum samples collected prospectively from 100 incident lung cancer cases and 96 controls (matched on age, gender, and date of collection) nested within an ongoing high-risk cohort. The CA-FISH assay was aimed at four DNA targets: epidermal growth factor receptor, MYC, 5p15, and CEP 6. The sensitivity of a positive CA-FISH assay (abnormal for two or more of the four markers) for lung cancer was substantially higher for samples collected within 18 months (76% sensitivity) than for samples collected more than 18 months (31%) before lung cancer diagnosis. Sensitivity was higher for squamous cell cancers (94%) than for other histologic types (69%). CA-FISH specificity based on samples collected within 18 months before diagnosis was 88%. The adjusted odds ratio (OR) of lung cancer for specimens collected within 18 months before a cancer diagnosis was higher for the CA-FISH assay [OR, 29.9; 95% confidence interval (95% CI), 9.5-94.1] than for previously studied ORs of cytologic atypia (OR, 1.8; 95% CI, 1.3-2.6) and gene promoter methylation (OR, 6.5; 95% CI, 1.2-35.5). Whether CA-FISH is an indicator of extreme risk for incident lung cancer or detects exfoliated cancer cells is unknown. The apparent promise of CA-FISH in sputum for assessing lung cancer risk and/or for lung cancer early detection now needs to be validated in a clinical screening trial. Cancer Prev Res; 3(4); 447–53. ©2010 AACR.

  A Margariti , A Zampetaki , Q Xiao , B Zhou , E Karamariti , D Martin , X Yin , M Mayr , H Li , Z Zhang , E De Falco , Y Hu , G Cockerill , Q Xu and L. Zeng
 

Rationale: Histone deacetylase (HDAC)7 is expressed in the early stages of embryonic development and may play a role in endothelial function.

Objective: This study aimed to investigate the role of HDAC7 in endothelial cell (EC) proliferation and growth and the underlying mechanism.

Methods and Results: Overexpression of HDAC7 by adenoviral gene transfer suppressed human umbilical vein endothelial cell (HUVEC) proliferation by preventing nuclear translocation of β-catenin and downregulation of T-cell factor-1/Id2 (inhibitor of DNA binding 2) and cyclin D1, leading to G1 phase elongation. Further assays with the TOPFLASH reporter and quantitative RT-PCR for other β-catenin target genes such as Axin2 confirmed that overexpression of HDAC7 decreased β-catenin activity. Knockdown of HDAC7 by lentiviral short hairpin RNA transfer induced β-catenin nuclear translocation but downregulated cyclin D1, cyclin E1 and E2F2, causing HUVEC hypertrophy. Immunoprecipitation assay and mass spectrometry analysis revealed that HDAC7 directly binds to β-catenin and forms a complex with 14-3-3 , , and proteins. Vascular endothelial growth factor treatment induced HDAC7 degradation via PLC-IP3K (phospholipase C–inositol-1,4,5-trisphosphate kinase) signal pathway and partially rescued HDAC7-mediated suppression of proliferation. Moreover, vascular endothelial growth factor stimulation suppressed the binding of HDAC7 with β-catenin, disrupting the complex and releasing β-catenin to translocate into the nucleus.

Conclusions: These findings demonstrate that HDAC7 interacts with β-catenin keeping ECs in a low proliferation stage and provides a novel insight into the mechanism of HDAC7-mediated signal pathways leading to endothelial growth.

  F Fleissner , V Jazbutyte , J Fiedler , S. K Gupta , X Yin , Q Xu , P Galuppo , S Kneitz , M Mayr , G Ertl , J Bauersachs and T. Thum
 

Rationale: The endogenous nitric oxide synthase inhibitor asymmetrical dimethylarginine (ADMA) is increased in patients with coronary artery disease and may regulate function of circulating angiogenic progenitor cells (APCs) by small regulatory RNAs.

Objectives: To study the role of microRNAs in ADMA-mediated impairment of APCs.

Methods and Results: By using microarray analyses, we established microRNA expression profiles of human APCs. We used ADMA to induce APC dysfunction and found 16 deregulated microRNAs. We focused on miR-21, which was 3-fold upregulated by ADMA treatment. Overexpression of miR-21 in human APCs impaired migratory capacity. To identify regulated miR-21 targets, we used proteome analysis, using difference in-gel electrophoresis followed by mass spectrometric analysis of regulated proteins. We found that transfection of miR-21 precursors significantly repressed superoxide dismutase 2 in APCs, which resulted in increased intracellular reactive oxygen species concentration and impaired nitric oxide bioavailability. MiR-21 further repressed sprouty-2, leading to Erk Map kinase–dependent reactive oxygen species formation and APC migratory defects. Small interference RNA–mediated superoxide dismutase 2 or sprouty-2 reduction also increased reactive oxygen species formation and impaired APC migratory capacity. ADMA-mediated reactive oxygen species formation and APC dysfunction was rescued by miR-21 blockade. APCs from patients with coronary artery disease and high ADMA plasma levels displayed >4-fold elevated miR-21 levels, low superoxide dismutase 2 expression, and impaired migratory capacity, which could be normalized by miR-21 antagonism.

Conclusions: We identified a novel miR-21–dependent mechanism of ADMA-mediated APC dysfunction. MiR-21 antagonism therefore emerges as an interesting strategy to improve dysfunctional APCs in patients with coronary artery disease.

  J Tian , J Jeudy , M. F Smith , A Jimenez , X Yin , P. A Bruce , P Lei , A Turgeman , A Abbo , R Shekhar , M Saba , S Shorofsky and T. Dickfeld
  Background—

Advances in contrast-enhanced multidetector CT enable detailed characterization of the left ventricular myocardium. Myocardial scar and border zone (BZ), as the target of ventricular tachycardia ablations, displays abnormal anatomic, dynamic, and perfusion characteristics during first-pass CT. This study assessed how contrast-enhanced CT can predict voltage-defined scar and BZ and integrate its scar reconstructions into clinical mapping systems to guide ventricular tachycardia ablations.

Methods and Results—

Eleven patients with ischemic cardiomyopathy underwent contrast-enhanced CT before ventricular tachycardia ablation. Segmental anatomic (end-systolic and end-diastolic wall thickness), dynamic (wall thickening, wall motion), and perfusion (hypoenhancement) characteristics were evaluated. Receiver operating characteristic curves assessed the ability of CT to determine voltage-defined scar and BZ segments. Three-dimensional epi- and endocardial surfaces and scar borders were reconstructed, coregistered, and compared to voltages using a 17-segment model. Abnormal anatomic, dynamic, and perfusion data correlated well with abnormal (<1.5 mV) endocardial voltages (r=0.77). Three-dimensional reconstruction integrated into the clinical mapping system (registration accuracy, 3.31±0.52 mm) allowed prediction of homogenous abnormal voltage (<1.5 mV) in 81.7% of analyzed segments and correctly displayed transmural extent and intramural scar location. CT hypoperfusion correlated best with scar and BZ areas and encompassed curative ablations in 82% cases.

Conclusions—

Anatomic, dynamic, and perfusion imaging using contrast-enhanced CT allows characterization of left ventricular anatomy and 3D scar and BZ substrate. Integration of reconstructed 3D data sets into clinical mapping systems supplements information of voltage mapping and may enable new image approaches for substrate-guided ventricular tachycardia ablation.

  M Mayr , D Grainger , U Mayr , A. S Leroyer , G Leseche , A Sidibe , O Herbin , X Yin , A Gomes , B Madhu , J. R Griffiths , Q Xu , A Tedgui and C. M. Boulanger
 

Background— Microparticles (MPs) with procoagulant activity are present in human atherosclerosis, but no detailed information is available on their composition.

Methods and Results— To obtain insights into the role of MPs in atherogenesis, MP proteins were identified by tandem mass spectrometry, metabolite profiles were determined by high-resolution nuclear magnetic resonance spectroscopy, and antibody reactivity was assessed against combinatorial antigen libraries. Plaque MPs expressed surface antigens consistent with their leukocyte origin, including major histocompatibility complex classes I and II, and induced a dose-dependent stimulatory effect on T-cell proliferation. Notably, taurine, the most abundant free organic acid in human neutrophils, which scavenges myeloperoxidase-catalyzed free radicals, was highly enriched in plaque MPs. Moreover, fluorescent labeling of proteins on the MP surface suggested immunoglobulins to be trapped inside, which was confirmed by flow cytometry analysis on permeabilized and nonpermeabilized plaque MPs. Colabeling for CD14 and IgG established that more than 90% of the IgG containing MPs were CD14+, indicating a macrophage origin. Screening against an antigen library revealed that the immunologic profiles of antibodies in MPs were similar to those found in plaques but differed profoundly from antibodies in plasma and unexpectedly, showed strong reactions with oligosaccharide antigens, in particular blood group antigen A.

Conclusions— This study provides the first evidence that immunoglobulins are present within MPs derived from plaque macrophages, that the portfolio of plaque antibodies is different from circulating antibodies in plasma, and that anticarbohydrate antibodies are retained in human atherosclerotic lesions.

  A. K Pandey , X Yin , R. B Schiffer , J. C Hutson , D. M Stocco , P Grammas and X. Wang
 

Recent studies suggested an involvement of thromboxane A2 in cyclooxygenase-2-dependent inhibition of steroidogenic acute regulatory (StAR) gene expression. The present study further investigated the role of thromboxane A2 receptor in StAR gene expression and steroidogenesis in testicular Leydig cells. The thromboxane A2 receptor was detected in several Leydig cell lines. Blocking thromboxane A2 binding to the receptor using specific antagonist SQ29548 or BM567 resulted in dose-dependent increases in StAR protein and steroid production in MA-10 mouse Leydig cells. The results were confirmed with Leydig cells isolated from rats. StAR promoter activity and StAR mRNA level in the cells were also increased after the treatments, suggesting an involvement of the thromboxane A2 receptor in StAR gene transcription. Furthermore study indicated that blocking the thromboxane A2 receptor reduced dosage sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1 protein, a transcriptional repressor of StAR gene expression. Specific binding of the antagonists to the receptors on cellular membrane was demonstrated by binding assays using 3H-SQ29548 and binding competition between 3H-SQ29548 and BM567. Whereas SQ29548 enhanced cAMP-induced StAR gene expression, in the absence of cAMP, it was unable to increase StAR protein and steroidogenesis. However, when the receptor was blocked by the antagonist, subthreshold levels of cAMP were able to induce maximal levels of StAR protein expression, suggesting that blocking the thromboxane A2 receptor increase sensitivity of MA-10 cells to cAMP stimulation. Taken together, the results from the present and previous studies suggest an autocrine loop, involving cyclooxygenase-2, thromboxane A synthase, and thromboxane A2 and its receptor, in cyclooxygenase-2-dependent inhibition of StAR gene expression.

  T Geng , P Li , M Okutsu , X Yin , J Kwek , M Zhang and Z. Yan
 

Endurance exercise stimulates peroxisome proliferator-activated receptor coactivator-1 (PGC-1) expression in skeletal muscle, and forced expression of PGC-1 changes muscle metabolism and exercise capacity in mice. However, it is unclear if PGC-1 is indispensible for endurance exercise-induced metabolic and contractile adaptations in skeletal muscle. In this study, we showed that endurance exercise-induced expression of mitochondrial enzymes (cytochrome oxidase IV and cytochrome c) and increases of platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31)-positive endothelial cells in skeletal muscle, but not IIb-to-IIa fiber-type transformation, were significantly attenuated in muscle-specific Pgc-1 knockout mice. Interestingly, voluntary running effectively restored the compromised mitochondrial integrity and superoxide dismutase 2 (SOD2) protein expression in skeletal muscle in Pgc-1 knockout mice. Thus, PGC-1 plays a functional role in endurance exercise-induced mitochondrial biogenesis and angiogenesis, but not IIb-to-IIa fiber-type transformation in mouse skeletal muscle, and the improvement of mitochondrial morphology and antioxidant defense in response to endurance exercise may occur independently of PGC-1 function. We conclude that PGC-1 is required for complete skeletal muscle adaptations induced by endurance exercise in mice.

 
 
 
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