Shu Ye

Publications (64)439.35 Total impact

• Article: An Important Role of Matrix Metalloproteinase-8 in Angiogenesis in Vitro and in Vivo.

  Changcun Fang, Guanmei Wen, Li Zhang, Luyang Lin, Andrew Moore, Shuming Wu, Shu Ye, Qingzhong Xiao
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  ABSTRACT: AIMS: Growing evidence suggests a close association of plaque angiogenesis with atherosclerotic plaque formation and progression, and an important role of matrix metalloproteinase (MMP) in angiogenesis and atherosclerosis. We attempted to investigate the functional involvements of MMP8 in angiogenesis.Methods and ResultsKnockdown of MMP8 in human umbilical vein endothelial cells (HuVECs) with MMP-8 shRNA lentivirus resulted in a decrease of in vitro capillary-like network formation, cell proliferation and migration, and impaired its capacity of in vivo angiogenesis. Less nuclear accumulation of β-catenin and lower β-catenin target gene expression levels were observed in the HuVECs expressing lower levels of endogenous MMP8. Knockdown of endogenous MMP8 in HuVECs down-regulated platelet/endothelial cell adhesion molecule-1 (PECAM-1) expression by converting less angiotensin I to II, which is an inducer for PECAM-1 gene expression. Aortic rings isolated from MMP8(-/-)/apoE(-/-) mice had less endothelial cell sprouting, and endothelial cells in MMP8(-/-)/apoE(-/-) mice had lower ability to migrate into Matrigel plugs and less capacity of proliferation and angiogenesis. Moreover, immunohistochemical analyses revealed that MMP8 was expressed in microvessels within human atherosclerotic plaques and aneurysm. Finally, analyses of MMP8(-/-)/apoE(-/-) and MMP8(+/+)/apoE(-/-) mice fed a Western diet for 12 weeks showed that MMP8-deficient mice had small lesion size and less endothelial cells within atherosclerotic lesions. CONCLUSIONS: We demonstrated for the first time that MMP8 plays an important role in angiogenesis in vitro and in vivo. Our findings provide new insights into the molecular mechanisms of plaque angiogenesis and suggest that MMP8 is a potential therapeutic target of cardiovascular diseases.
  Cardiovascular research 03/2013; · 5.80 Impact Factor
• Article: ADAMTS7 Cleavage and Vascular Smooth Muscle Cell Migration Is Affected by a Coronary-Artery-Disease-Associated Variant.

  Xiangyuan Pu, Qingzhong Xiao, Stefan Kiechl, Kenneth Chan, Fu Liang Ng, Shivani Gor, Robin N Poston, Changcun Fang, Ashish Patel, Ece C Senver, Sue Shaw-Hawkins, Johann Willeit, Chuanju Liu, Jianhua Zhu, Arthur T Tucker, Qingbo Xu, Mark J Caulfield, Shu Ye
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  ABSTRACT: Recent genome-wide association studies have revealed an association between variation at the ADAMTS7 locus and susceptibility to coronary artery disease (CAD). Furthermore, in a population-based study cohort, we observed an inverse association between atherosclerosis prevalence and rs3825807, a nonsynonymous SNP (A to G) leading to a Ser-to-Pro substitution in the prodomain of the protease ADAMTS7. In light of these data, we sought a mechanistic explanation for this association. We found that ADAMTS7 accumulated in smooth muscle cells in coronary and carotid atherosclerotic plaques. Vascular smooth muscle cells (VSMCs) of the G/G genotype for rs3825807 had reduced migratory ability, and conditioned media of VSMCs of the G/G genotype contained less of the cleaved form of thrombospondin-5, an ADAMTS7 substrate that had been shown to be produced by VSMCs and inhibit VSMC migration. Furthermore, we found that there was a reduction in the amount of cleaved ADAMTS7 prodomain in media conditioned by VSMCs of the G/G genotype and that the Ser-to-Pro substitution affected ADAMTS7 prodomain cleavage. The results of our study indicate that rs3825807 has an effect on ADAMTS7 maturation, thrombospondin-5 cleavage, and VSMC migration, with the variant associated with protection from atherosclerosis and CAD rendering a reduction in ADAMTS7 function.
  The American Journal of Human Genetics 02/2013; · 10.60 Impact Factor
• Article: Functional Involvements of Heterogeneous Nuclear Ribonucleoprotein A1 in Smooth Muscle Differentiation from Stem Cells in Vitro and in Vivo.

  Yuan Huang, Luyang Lin, Xiaotian Yu, Guanmei Wen, Xiangyuan Pu, Hanqing Zhao, Changcun Fang, Jianhua Zhu, Shu Ye, Li Zhang, Qingzhong Xiao
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  ABSTRACT: To investigate the functional involvements of heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) in smooth muscle cell (SMC) differentiation from stem cells, embryonic stem (ES) cells were cultivated on collagen IV-coated plates to allow for SMC differentiation. We found that hnRNPA1 gene and protein expression was up-regulated significantly during differentiation, and co-expressed with SMC differentiation markers in the stem cell-derived SMCs as well as embryonic SMCs of 12.5 days of mouse embryos. hnRNPA1 knockdown resulted in down-regulation of smooth muscle markers and transcription factors, while enforced expression of hnRNPA1 enhanced the expression of these genes. Importantly, knockdown of hnRNPA1 also resulted in impairment of SMC differentiation in vivo. Moreover, we demonstrated that hnRNPA1 could transcriptionally regulate SMC gene expression through direct binding to promoters of Acta2 and Tagln genes by using luciferase and chromatin immunoprecipitation assays. We further demonstrated that the binding sites for serum response factor (SRF), a well-investigated SMC transcription factor, within the promoter region of the Acta2 and Tagln genes was responsible for hnRNPA1-mediated Acta2 and Tagln gene expression by using in vitro site-specific mutagenesis and luciferase activity analyses. Finally, we also demonstrated that hnRNPA1 up-regulated the expression of SRF, myocyte-specific enhancer factor 2C (MEF2C) and myocardin through transcriptional activation and direct binding to promoters of the SRF, MEF2c and Myocd genes. Our findings demonstrated that hnRNPA1 plays a functional role in SMC differentiation from stem cells in vitro and in vivo. This indicates that hnRNPA1 is a potential modulating target for deriving SMCs from stem cells and cardiovascular regenerative medicine.
  Stem Cells 01/2013; · 7.78 Impact Factor
• Article: Association Between the Chromosome 9p21 Locus and Angiographic Coronary Artery Disease Burden: A Collaborative Meta-Analysis.

  Kenneth Chan, Riyaz S Patel, Paul Newcombe, Christopher P Nelson, Atif Qasim, Stephen E Epstein, Susan Burnett, Viola L Vaccarino, A Maziar Zafari, Svati H Shah, [......], Akinori Kimura, Wei-Feng Shen, Iain A Simpson, Stanley L Hazen, Benjamin D Horne, Elizabeth R Hauser, Arshed A Quyyumi, Muredach P Reilly, Nilesh J Samani, Shu Ye
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  ABSTRACT: OBJECTIVES: The aim of this study was to ascertain the relationship of 9p21 locus with: 1) angiographic coronary artery disease (CAD) burden; and 2) myocardial infarction (MI) in individuals with underlying CAD. BACKGROUND: Chromosome 9p21 variants have been robustly associated with coronary heart disease, but questions remain on the mechanism of risk, specifically whether the locus contributes to coronary atheroma burden or plaque instability. METHODS: We established a collaboration of 21 studies consisting of 33,673 subjects with information on both CAD (clinical or angiographic) and MI status along with 9p21 genotype. Tabular data are provided for each cohort on the presence and burden of angiographic CAD, MI cases with underlying CAD, and the diabetic status of all subjects. RESULTS: We first confirmed an association between 9p21 and CAD with angiographically defined cases and control subjects (pooled odds ratio [OR]: 1.31, 95% confidence interval [CI]: 1.20 to 1.43). Among subjects with angiographic CAD (n = 20,987), random-effects model identified an association with multivessel CAD, compared with those with single-vessel disease (OR: 1.10, 95% CI: 1.04 to 1.17)/copy of risk allele). Genotypic models showed an OR of 1.15, 95% CI: 1.04 to 1.26 for heterozygous carrier and OR: 1.23, 95% CI: 1.08 to 1.39 for homozygous carrier. Finally, there was no significant association between 9p21 and prevalent MI when both cases (n = 17,791) and control subjects (n = 15,882) had underlying CAD (OR: 0.99, 95% CI: 0.95 to 1.03)/risk allele. CONCLUSIONS: The 9p21 locus shows convincing association with greater burden of CAD but not with MI in the presence of underlying CAD. This adds further weight to the hypothesis that 9p21 locus primarily mediates an atherosclerotic phenotype.
  Journal of the American College of Cardiology 01/2013; · 14.16 Impact Factor
• Article: Chromosome 1p13 genetic variants antagonize the risk of myocardial infarction associated with high ApoB serum levels.

  Bruna Gigante, Karin Leander, Max Vikström, Shu Ye, Ulf de Faire
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  ABSTRACT: Genetic variation at 1p13 modulates serum lipid levels and the risk of coronary heart disease through the regulation of serum lipid levels. Here we investigate if the interaction between genetic variants at 1p13 and serum lipid levels affects the risk of non-fatal myocardial infarction (MI) in the Stockholm Heart Epidemiology Program (SHEEP), a large population based case control study. In the present study only non fatal MI cases (n = 1213, men/women: 852/361) and controls (n = 1516, men/women =1054/507) matched by age, sex and residential area, were included. Three SNPs 12740374 G/T, rs599839A/G and rs646776T/C mapping at 1p13 were analysed for association with serum lipid levels and the risk of MI by a weighted least square regression and logistic regression analyses, respectively. To analyse the effect of the interaction between genetic variants and serum lipid levels on the risk of MI, we applied the biological model of interaction that estimates the difference in risk, expressed as OR (95%CI), observed in the presence and in the absence of both exposures. One derived measure is the Synergy index (S) and 95%CI, where S > 1 indicates synergy and S < 1 antagonism between the two interaction terms. Rs12740374G/T and rs646776T/C were in strong linkage disequilibrium (LD) (r2 = 0.99), therefore only rs599839A/G and rs646776 were included in the analysis. Consistently with published data, presence of the rare genotypes was associated with reduced total-, LDL-cholesterol and ApoB serum levels (all p < 0.05) as compared to the reference genotype, but was not associated with the risk of MI.However, the increased risk of MI observed in individual exposed to high (≥75th percentile) serum lipid levels was offset in subjects carrying the rare alleles G and C. In particular, the risk of MI associated with high ApoB serum levels OR (95%CI) 2.27 (1.86-2.77) was reduced to 1.76 (1.33-2.34) in the presence of the G allele at rs599839 with an S of 0.47 (0.20-0.90). These results indicate that an antagonism between ApoB serum levels and genetic variants at 1p13 contributes to reduce the risk of non-fatal MI in the presence of high ApoB serum levels.
  BMC Cardiovascular Disorders 10/2012; 12:90. · 1.52 Impact Factor
• Article: A Functional Role of Matrix Metalloproteinase-8 in Stem/Progenitor Cell Migration and Their Recruitment into Atherosclerotic Lesions.

  Qingzhong Xiao, Feng Zhang, Luyang Lin, Changcun Fang, Guanmei Wen, Tsung-Neng Tsai, Xiangyuan Pu, David Sims, Zhongyi Zhang, Xiaoke Yin, Binia Thomaszewski, Boris Schmidt, Manuel Mayr, Ken Suzuki, Qingbo Xu, Shu Ye
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  ABSTRACT: Rationale: Accumulating evidence indicates that stem/progenitor cells represent an important source of cells in atheromas and contribute to lesion formation and progression. Objective: We investigated whether matrix metalloproteinase-8 (MMP8) played a role in stem/progenitor cell migration and their recruitment into atheromas. Methods and Results: We found that stem/progenitor cells in atheromas expressed MMP8 and that MMP8 knockout significantly reduced stem/progenitor cell numbers in atherosclerotic lesions in ApoE deficient mice fed a Western diet. Further in vivo experiments showed that ApoE(-/-)/MMP8(-/-) mice injected with stem cells isolated from bone marrows of ApoE(-/-)/MMP8(-/-) mice had fewer stem/progenitor cells in atheromas and smaller lesions than ApoE(-/-)/MMP8(-/-) mice injected with stem cells isolated from bone marrows of ApoE(-/-)/MMP8(+/+) mice. Ex vivo experiments showed MMP8 deficiency inhibited the ability of stem/progenitor cells to migrate from the arterial lumen and from the adventitia, into atherosclerotic lesions. In vitro assays indicated that MMP8 facilitated stem/progenitor cell migration across endothelial cells and through Matrigel or collagen I. We also found that MMP8 cleaved a-disintegrin-and-metalloproteinase-domain-10 (ADAM10) and that MMP8 deficiency reduced mature ADAM10 on stem/progenitor cells. Knockdown of MMP8 or incubation with the ADAM10 inhibitor GI254023X decreased E-cadherin shedding on stem/progenitor cells. The decrease in migratory ability of stem/progenitor cells with MMP8 knockdown was reduced by incubation of such cells with culture supernatant from stem/progenitor cells without MMP8 knockdown, and this compensatory effect was abolished by an antibody against soluble E-cadherin. Conclusions: MMP8 plays an important role in stem/progenitor cell migration and their recruitment into atherosclerotic lesions.
  Circulation Research 10/2012; · 9.49 Impact Factor
• Article: Functional analyses of coronary artery disease associated variation on chromosome 9p21 in vascular smooth muscle cells.

  Anna Motterle, Xiangyuan Pu, Harriet Wood, Qingzhong Xiao, Shivani Gor, Fu Liang Ng, Kenneth Chan, Frank Cross, Beski Shohreh, Robin N Poston, Arthur T Tucker, Mark J Caulfield, Shu Ye
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  ABSTRACT: Variation on chromosome 9p21 is associated with risk of coronary artery disease (CAD). This genomic region contains the CDKN2A and CDKN2B genes which encode the cell cycle regulators p16(INK4a), p14(ARF) and p15(INK4b) and the ANRIL gene which encodes a non-coding RNA. Vascular smooth muscle cell (VSMC) proliferation plays an important role in the pathogenesis of atherosclerosis which causes CAD. We ascertained whether 9p21 genotype had an influence on CDKN2A/CDKN2B/ANRIL expression levels in VSMCs, VSMC proliferation and VSMC content in atherosclerotic plaques. Immunohistochemical examination showed that VSMCs in atherosclerotic lesions expressed p16(INK4a), p14(ARF) and p15(INK4b). Analyses of primary cultures of VSMCs showed that the 9p21 risk genotype was associated with reduced expression of p16(INK4a), p15(INK4b) and ANRIL (P = 1.2 × 10(-5), 1.4 × 10(-2) and 3.1 × 10(-9)) and with increased VSMC proliferation (P = 1.6 × 10(-2)). Immunohistochemical analyses of atherosclerotic plaques revealed an association of the risk genotype with reduced p15(INK4b) levels in VSMCs (P = 3.7 × 10(-2)) and higher VSMC content (P = 5.6 × 10(-4)) in plaques. The results of this study indicate that the 9p21 variation has an impact on CDKN2A and CDKN2B expression in VSMCs and influences VMSC proliferation, which likely represents an important mechanism for the association between this genetic locus and susceptibility to CAD.
  Human Molecular Genetics 06/2012; 21(18):4021-9. · 7.64 Impact Factor
• Article: Nrf3-Pla2g7 interaction plays an essential role in smooth muscle differentiation from stem cells.

  Qingzhong Xiao, Anna E Pepe, Gang Wang, Zhenling Luo, Li Zhang, Lingfang Zeng, Zhongyi Zhang, Yanhua Hu, Shu Ye, Qingbo Xu
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  ABSTRACT: Phospholipase A2, group 7 (Pla2g7) is an important mediator in cardiovascular development and diseases because of its divergent physiological and pathological functions in inflammation and oxidative stress. However, little is known about the functional role of Pla2g7 in smooth muscle cell (SMC) differentiation from stem cells. In the present study, embryonic stem cells were cultivated on collagen IV-coated plates to allow SMC differentiation. Pla2g7 gene expression and activity were upregulated significantly following 4 to 14 days of cell differentiation and colocalized with SMC differentiation markers in the differentiated SMCs. Knockdown of Pla2g7 resulted in downregulation of smooth muscle-specific markers in vitro and impairment of SMC differentiation in vivo, whereas enforced expression of Pla2g7 enhanced SMC differentiation and increased reactive oxygen species generation. Importantly, enforced expression of Pla2g7 significantly increased the binding of serum response factor to SMC differentiation gene promoters, resulting in SMC differentiation, which was abolished by free radical scavenger and flavoprotein inhibitor of NADPH oxidase but not hydrogen peroxide inhibitor. Moreover, we demonstrated that nuclear factor erythroid 2-related factor 3 (Nrf3) regulates Pla2g7 gene expression through direct binding to the promoter regions of Pla2g7 gene. Our findings demonstrated that Pla2g7 plays a crucial physiological role in SMC differentiation from stem cells, and the fine interactions between Nrf3 and Pla2g7 are essential for SMC differentiation.
  Arteriosclerosis Thrombosis and Vascular Biology 03/2012; 32(3):730-44. · 6.37 Impact Factor
• Article: Comment on: "A promoter polymorphism (rs17222919, -1316T/G) of ALOX5AP is associated with intracerebral hemorrhage in Korean population" by Hwan Kim D. et al. [Prostaglandins Leukot. Essent. Fatty Acids 85 (2011) 115-120].

  Antonio Lapenna, Ross C Laxton, Shu Ye
  Prostaglandins Leukotrienes and Essential Fatty Acids 02/2012; 86(3):135-6. · 3.37 Impact Factor
• Article: Functional impact of heterogeneous nuclear ribonucleoprotein A2/B1 in smooth muscle differentiation from stem cells and embryonic arteriogenesis.

  Gang Wang, Qingzhong Xiao, Zhenling Luo, Shu Ye, Qingbo Xu
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  ABSTRACT: Heterogeneous nuclear ribonucleoproteins (hnRNPs) play various roles in transcriptional and post-transcriptional modulation of gene expression. However, it remains unclear if hnRNPs are associated with smooth muscle cell (SMC) differentiation from stem cells and embryonic arteriogenesis. In this study, mouse embryonic stem (ES) cells were cultivated on collagen IV-coated plates and smooth muscle differentiation medium. We found that hnRNPA2/B1 gene and protein expression was significantly up-regulated following 3-7 days of cell differentiation. hnRNPA2/B1 knockdown resulted in down-regulation of specific smooth muscle markers and transcription factors, whereas enforced expression of hnRNPA2/B1 enhanced the expression of these genes. Moreover, we demonstrated by using luciferase and chromatin immunoprecipitation assays that hnRNPA2/B1 could transcriptionally regulate SMC gene expression through direct binding to promoters of Smαa and Sm22α genes. We further demonstrated that chromobox protein homolog gene 3, a previously identified SMC differentiation regulatory nuclear protein, is required for hnRNPA2/B1-mediated SMC differentiation gene expression. Importantly, specifically designed Hnrnpa2/b1 morpholinos for in vivo knockdown could inhibit the migration and differentiation of neural crest cells into SMCs in chick embryos. This resulted in the maldevelopment of branchial arch arteries and increased embryo lethality at a later developmental stage. Our findings demonstrated that hnRNPA2/B1 plays a functional role in SMC differentiation from stem cells in vitro and embryonic branchial arch artery development. This indicates that hnRNPA2/B1 is a potential modulating target for deriving SMCs from stem cells and cardiovascular regenerative medicine.
  Journal of Biological Chemistry 12/2011; 287(4):2896-906. · 4.77 Impact Factor
• Article: Association of variation at the ABO locus with circulating levels of soluble intercellular adhesion molecule-1, soluble P-selectin, and soluble E-selectin: a meta-analysis.

  Stefan Kiechl, Guillaume Paré, Maja Barbalic, Lu Qi, Josée Dupuis, Abbas Dehghan, Joshua C Bis, Ross C Laxton, Qingzhong Xiao, Enzo Bonora, Johann Willeit, Qingbo Xu, Jacqueline C M Witteman, Daniel Chasman, Russell P Tracy, Christie M Ballantyne, Paul M Ridker, Emelia J Benjamin, Shu Ye
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  ABSTRACT: Circulating levels of soluble intercellular adhesion molecule-1, soluble P-selectin, and soluble E-selectin have been associated with variation at the ABO locus. To evaluate these associations and the effect sizes, we performed a meta-analysis with new and previous reported data for polymorphism rs579459. Compared with major allele homozygotes, heterozygotes and minor allele homozygotes had 4.6% (95% CI, 3.4%-5.8%, P=7.3 × 10(-14)) and 7.2% (95% CI, 4.7%-9.7%, P=1.5 × 10(-8)), respectively, lower soluble intercellular adhesion molecule-1 levels (n=33 671). An allele dose-dependent association also was observed for soluble P-selectin (n=4921) with heterozygotes and minor allele homozygotes having 11.5% (95% CI, 7.2%-15.8%, P=1.7 × 10(-7)) and 18.6% (95% CI, 9.1%-28.1%, P=1.2 × 10(-4)), respectively, lower levels than in major allele homozygotes. A larger effect size, again consistent with an additive genetic model, was seen for soluble E-selectin (n=2860) whose level was 25.6% (95% CI, 19.0%-32.2%, P=2.1 × 10(-14)) lower in heterozygotes and 43.3% (95% CI, 36.9%-49.3%, P=4.3 × 10(-42)) lower in minor allele homozygotes than in major allele homozygotes. The data support the association of variation at the ABO locus with soluble intercellular adhesion molecule-1, soluble P-selectin, and soluble E-selectin levels.
  Circulation Cardiovascular Genetics 12/2011; 4(6):681-6. · 6.11 Impact Factor
• Article: Influence of matrix metalloproteinase-12 on fibrinogen level.

  Anna Motterle, Qingzhong Xiao, Stefan Kiechl, Sylvia L F Pender, Gareth E Morris, Johann Willeit, Mark J Caulfield, Shu Ye
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  ABSTRACT: In vitro studies have shown that matrix metalloproteinase-12 (MMP12) can degrade fibrinogen, a clotting factor whose level predicts risk of advanced atherosclerosis and myocardial infarction. In this study, we found that mean plasma fibrinogen level was approximately 10-fold higher in MMP12 knockout mice than wildtype mice (p=0.0006). Differential allelic expression analysis of human MMP12 gene polymorphism rs17368582 in human vascular tissues showed an allele-specific effect on MMP12 expression, with one allele (T) having 1.6 fold higher expression level than the other allele (C) (p=0.0006). In a population cohort, we found that individuals homozygous for the MMP12 low expression allele had higher plasma fibrinogen levels (2.95 mg/mL compared with 2.61 mg/mL in other individuals, p=0.029) and increased risk of advanced atherosclerosis [odds ratio 6.3 (95% CI 1.9-20.8), p=0.003] and myocardial infarction [hazard ratio 5.6 (95% CI 1.7-18.3), p=0.005]. In summary, our study in mouse and humans provides in vivo evidence of an effect of MMP12 on fibrinogen level.
  Atherosclerosis 11/2011; 220(2):351-4. · 3.79 Impact Factor
• Article: Genetic determinants of coronary heart disease: new discoveries and insights from genome-wide association studies.

  Riyaz S Patel, Shu Ye
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  ABSTRACT: With the advent of the Human Genome Project and the genomic era, new tools and methodologies have revitalised genetic research into coronary heart disease (CHD). Unprecedented collaborative efforts are discovering novel risk variants for CHD, with most in hitherto unknown molecular pathways. These findings have stimulated a plethora of follow-up of functional and risk prediction studies to mine this wealth of new data. This review will explore the current state of knowledge of the genetic basis of CHD, with an emphasis on recent genomic studies and how these may eventually lead to the promised goals of new therapeutics and personalised medicine.
  Heart (British Cardiac Society) 09/2011; 97(18):1463-73. · 4.22 Impact Factor
• Source

  Available from: Richard W Morris

  Article: Comparative analysis of genome-wide association studies signals for lipids, diabetes, and coronary heart disease: Cardiovascular Biomarker Genetics Collaboration.

  Aspasia Angelakopoulou, Tina Shah, Reecha Sofat, Sonia Shah, Diane J Berry, Jackie Cooper, Jutta Palmen, Ioanna Tzoulaki, Andrew Wong, Barbara J Jefferis, [......], Meena Kumari, Elina Hypponen, Chris Power, Steve E Humphries, Philippa J Talmud, Jackie Price, Richard W Morris, Shu Ye, Juan P Casas, Aroon D Hingorani
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  ABSTRACT: To evaluate the associations of emergent genome-wide-association study-derived coronary heart disease (CHD)-associated single nucleotide polymorphisms (SNPs) with established and emerging risk factors, and the association of genome-wide-association study-derived lipid-associated SNPs with other risk factors and CHD events. Using two case-control studies, three cross-sectional, and seven prospective studies with up to 25 000 individuals and 5794 CHD events we evaluated associations of 34 genome-wide-association study-identified SNPs with CHD risk and 16 CHD-associated risk factors or biomarkers. The Ch9p21 SNPs rs1333049 (OR 1.17; 95% confidence limits 1.11-1.24) and rs10757274 (OR 1.17; 1.09-1.26), MIA3 rs17465637 (OR 1.10; 1.04-1.15), Ch2q36 rs2943634 (OR 1.08; 1.03-1.14), APC rs383830 (OR 1.10; 1.02, 1.18), MTHFD1L rs6922269 (OR 1.10; 1.03, 1.16), CXCL12 rs501120 (OR 1.12; 1.04, 1.20), and SMAD3 rs17228212 (OR 1.11; 1.05, 1.17) were all associated with CHD risk, but not with the CHD biomarkers and risk factors measured. Among the 20 blood lipid-related SNPs, LPL rs17411031 was associated with a lower risk of CHD (OR 0.91; 0.84-0.97), an increase in Apolipoprotein AI and HDL-cholesterol, and reduced triglycerides. SORT1 rs599839 was associated with CHD risk (OR 1.20; 1.15-1.26) as well as total- and LDL-cholesterol, and apolipoprotein B. ANGPTL3 rs12042319 was associated with CHD risk (OR 1.11; 1.03, 1.19), total- and LDL-cholesterol, triglycerides, and interleukin-6. Several SNPs predicting CHD events appear to involve pathways not currently indexed by the established or emerging risk factors; others involved changes in blood lipids including triglycerides or HDL-cholesterol as well as LDL-cholesterol. The overlapping association of SNPs with multiple risk factors and biomarkers supports the existence of shared points of regulation for these phenotypes.
  European Heart Journal 07/2011; 33(3):393-407. · 10.48 Impact Factor
• Article: Chromobox protein homolog 3 is essential for stem cell differentiation to smooth muscles in vitro and in embryonic arteriogenesis.

  Qingzhong Xiao, Gang Wang, Xiaoke Yin, Zhenling Luo, Andriani Margariti, Lingfang Zeng, Manuel Mayr, Shu Ye, Qingbo Xu
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  ABSTRACT: Smooth muscle cell (SMC) differentiation is a critical process during cardiovascular formation and development, but the underlying molecular mechanism remains unclear. Here we demonstrated that chromobox protein homolog 3 (Cbx3) is crucial for SMC differentiation from stem cells and that the chromodomain and chromoshadow domain of Cbx3 are responsible for Cbx3-induced SMC differentiation. Moreover, we identified that 4 amino acids (165 to 168) within the chromoshadow domain of Cbx3 are key elements for Cbx3 interaction with Dia-1- and Cbx3-induced SMC differentiation. Mechanistically, we found that Cbx3 mediates SMC differentiation through modulating serum response factor (SRF) recruitment to the promoters of SMC genes, in which the interaction between Cbx3 and Dia-1/SRF plays a crucial role in this process. Moreover, our in vivo study demonstrated that the misexpression of Cbx3 within neural crest cells of chick embryos resulted in the death of chick embryos at early stages because of the maldevelopment of branchial arch arteries. Our findings suggest that the interaction between Cbx3 and Dia-1/SRF is essential for SMC differentiation from stem cells and for the development of functional cardiovascular system.
  Arteriosclerosis Thrombosis and Vascular Biology 06/2011; 31(8):1842-52. · 6.37 Impact Factor
• Article: Association of MMP8 gene variation with an increased risk of malignant melanoma.

  Tadeusz Dębniak, Anna Jakubowska, Pablo Serrano-Fernández, Grzegorz Kurzawski, Cezary Cybulski, Saleena Rani Chauhan, Ross C Laxton, Romuald Maleszka, Jan Lubinski, Shu Ye
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  ABSTRACT: Matrix metalloproteinases (MMPs) are implicated in the development of cancers including malignant melanoma (MM) and breast cancer. We tested the possible association of MMP1 and MMP8 gene variation with these two types of cancer. We genotyped 300 unselected patients with MM, 300 consecutive breast cancer cases, 300 controls for melanoma, and 300 controls for breast cancer (age-matched and sex-matched healthy adults with negative cancer family histories). Our study showed that the MMP8 gene rs11225395 polymorphism was associated with the risk of developing MM (odds ratio: 1.69; 95% confidence interval: 1.02-2.80; P=0.040) for the A/A genotype and 1.49 (95% confidence interval: 1.03-2.17; P=0.035) for the A/G genotype compared with the G/G genotype. The A allele was over-represented among MM cases compared with controls (odds ratio=1.54; P=0.017). In-vitro assays showed that the A allele had a higher promoter activity than the G allele in melanoma cells. No association was detected between this variant and breast cancer susceptibility. We found no strong association between MMP1 variation and the risk of MM or breast cancer. The finding of this study indicates an influence of MMP8 gene variation on melanoma susceptibility.
  Melanoma research 06/2011; 21(5):464-8. · 2.06 Impact Factor
• Article: Common variant on chromosome 9p21 predicts severity of coronary artery disease.

  Kenneth Chan, Anna Motterle, Ross C Laxton, Shu Ye
  Journal of the American College of Cardiology 03/2011; 57(13):1497-8; author reply 1498-9. · 14.16 Impact Factor
• Article: Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease.

  Heribert Schunkert, Inke R König, Sekar Kathiresan, Muredach P Reilly, Themistocles L Assimes, Hilma Holm, Michael Preuss, Alexandre F R Stewart, Maja Barbalic, Christian Gieger, [......], Alistair S Hall, Panos Deloukas, John R Thompson, Kari Stefansson, Robert Roberts, Unnur Thorsteinsdottir, Christopher J O'Donnell, Ruth McPherson, Jeanette Erdmann, Nilesh J Samani
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  ABSTRACT: We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 × 10⁻⁸ and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.
  Nature Genetics 03/2011; 43(4):333-8. · 35.53 Impact Factor
• Article: The genetics of epigenetics: is there a link with cardiovascular disease.

  Qingzhong Xiao, Shu Ye
  Heart (British Cardiac Society) 01/2011; 97(2):96-7. · 4.22 Impact Factor
• Source

  Available from: tswj.com

  Article: Toll-like receptors, their ligands, and atherosclerosis.

  Conrad P Hodgkinson, Shu Ye
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  ABSTRACT: Atherosclerosis is a disease characterized by inflammation in the arterial wall. Atherogenesis is dependent on the innate immune response involving activation of Toll-like receptors (TLRs) and the expression of inflammatory proteins. TLRs, which recognize various pathogen-associated molecular patterns, are expressed in various cell types within the atherosclerotic plaque. Microbial agents are associated with an increased risk of atherosclerosis and this is, in part, due to activation of TLRs. Recently considerable evidence has been provided suggesting that endogenous proteins promote atherosclerosis by binding to TLRs. In this review, we describe the role of TLRs in atherosclerosis with particular emphasis on those atherogenic endogenous proteins that have been implicated as TLR ligands.
  TheScientificWorldJOURNAL 01/2011; 11:437-53. · 1.66 Impact Factor