Publications by authors named "Qing K Wang"

112 Publications

Genetic association analysis between IL9 and coronary artery disease in a Chinese Han population.

Cytokine 2021 Nov 20;150:155761. Epub 2021 Nov 20.

Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address:

Interleukin-9 (IL-9) plays important role in coronary artery disease (CAD). However, the exact relationship between them is not explored yet. Here, four tag SNPs covering IL9 (rs31563, rs2069868, rs2069870 and rs31564) were selected to conduct case-control association analyses in a total of 3704 individuals from Chinese Han population (1863 CAD vs 1841 control). Results showed that: first, rs2069868 was associated with CAD combined with hypertension (P = 0.027); second, IL9 haplotype (CGAT) was associated with CAD (P = 0.035), and the combination genotype of "rs31563_CC/rs31564_TT" would remarkably decrease the risk of CAD (P = 0.001); third, significant associations were found between rs2069870 and decreased LDL-c levels and decreased total cholesterol levels, and between rs31563 and increased HDL-c levels (P < 0.05). Therefore, we conclude that IL9 might play a causal role in CAD by interacted with CAD traditional risk factors, which might confer a new way to improve the prevention and treatment of CAD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cyto.2021.155761DOI Listing
November 2021

Role of epigenetic m A RNA methylation in vascular development: mettl3 regulates vascular development through PHLPP2/mTOR-AKT signaling.

FASEB J 2021 05;35(5):e21465

Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, P.R. China.

N -methyladenosine (m6A) methylation is the most prevalent RNA modification, and it emerges as an important regulatory mechanism of gene expression involved in many cellular and biological processes. However, the role of m A methylation in vascular development is not clear. The m A RNA methylation is regulated by dynamic interplay among methyltransferases, binding proteins, and demethylases. Mettl3 is a member of the mettl3-mettl14 methyltransferase complex, referred to as writers that catalyze m6A RNA methylation. Here, we used CRISPR-Cas9 genome editing to develop two lines of knockout (KO) zebrafish for mettl3. Heterozygous mettl3 KO embryos show defective vascular development, which is directly visible in fli-EGFP and flk-EGFP zebrafish. Alkaline phosphatase staining and whole mount in situ hybridization with cdh5, and flk markers demonstrated defective development of intersegmental vessels (ISVs), subintestinal vessels (SIVs), interconnecting vessels (ICVs) and dorsal longitudinal anastomotic vessels (DLAV) in both heterozygous mettl3 and homozygous mettl3 KO zebrafish embryos. Similar phenotypes were observed in zebrafish embryos with morpholino knockdown (KD) of mettl3; however, the vascular defects were rescued fully by overexpression of constitutively active AKT1. KD of METTL3 in human endothelial cells inhibited cell proliferation, migration, and capillary tube formation. Mechanistically, mettl3 KO and KD significantly reduced the levels of m A RNA methylation, and AKT phosphorylation (S473) by an increase in the expression of phosphatase enzyme PHLPP2 and reduction in the phosphorylation of mTOR (S2481), a member of the phosphatidylinositol 3-kinase-related kinase family of protein kinases. These data suggest that m A RNA methylation regulates vascular development via PHLPP2/mTOR-AKT signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1096/fj.202000516RRDOI Listing
May 2021

Endothelial Cell Metabolic Memory Causes Cardiovascular Dysfunction In Diabetes.

Cardiovasc Res 2021 Jan 23. Epub 2021 Jan 23.

Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, P. R. China.

Aims: The aim of this study was to identify the molecular mechanism for hyperglycemia-induced metabolic memory in endothelial cells (ECs), and to show its critical importance to development of cardiovascular dysfunction in diabetes.

Methods And Results: Hyperglycemia induces increased nuclear factor-κB (NF-κB) signaling, upregulation of miR-27a-3p, downregulation of nuclear factor erythroid-2 related factor 2 (NRF2) expression, increased transforming growth factor-β (TGF-β) signaling, downregulation of miR-29, and induction of endothelial-to-mesenchymal transition (EndMT), all of which are memorized by ECs and not erased when switched to a low glucose condition, thereby causing perivascular fibrosis and cardiac dysfunction. Similar metabolic memory effects are found for production of nitric oxide (NO), generation of reactive oxygen species (ROS), and the mitochondrial oxygen consumption rate in two different types of ECs. The observed metabolic memory effects in ECs are blocked by NRF2 activator tert-butylhydroquinone and a miR-27a-3p inhibitor. In vivo, the NRF2 activator and miR-27a-3p inhibitor block cardiac perivascular fibrosis and restore cardiovascular function by decreasing NF-κB signaling, downregulating miR-27a-3p, upregulating NRF2 expression, reducing TGF-β signaling, and inhibiting EndMT during insulin treatment of diabetes in streptozotocin (STZ)-induced diabetic mice, whereas insulin alone does not improve cardiac function.

Conclusions: Our data indicate that disruption of hyperglycemia-induced EC metabolic memory is required for restoring cardiac function during treatment of diabetes, and identify a novel molecular signaling pathway of NF-κB/miR-27a-3p/NRF2/ROS/TGF-β/EndMT involved in metabolic memory.

Translational Perspective: Controversy exists on whether high blood glucose (hyperglycemia) induces metabolic memory that may cause long-lasting damaging cardiovascular complications in diabetic patients. Here, we demonstrate that hyperglycemia-induced metabolic memory in endothelial cells causes cardiac perivascular fibrosis and cardiac dysfunction in diabetes in mice, and identify NF-kB/miR-27a-3p/NRF2/ROS/TGF-β-EndMT as the signaling mechanism. We show that disruption of metabolic memory by a NRF2 activator or miR-27a-3p inhibitor is required to achieve therapeutic effect on cardiac dysfunction by insulin treatment of diabetes. Thus, inhibition of metabolic memory is a novel strategy to better prevent cardiovascular complications and improve the clinical outcome of diabetic patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cvr/cvab013DOI Listing
January 2021

TAGAP instructs Th17 differentiation by bridging Dectin activation to EPHB2 signaling in innate antifungal response.

Nat Commun 2020 04 20;11(1):1913. Epub 2020 Apr 20.

Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.

The TAGAP gene locus has been linked to several infectious diseases or autoimmune diseases, including candidemia and multiple sclerosis. While previous studies have described a role of TAGAP in T cells, much less is known about its function in other cell types. Here we report that TAGAP is required for Dectin-induced anti-fungal signaling and proinflammatory cytokine production in myeloid cells. Following stimulation with Dectin ligands, TAGAP is phosphorylated by EPHB2 at tyrosine 310, which bridges proximal Dectin-induced EPHB2 activity to downstream CARD9-mediated signaling pathways. During Candida albicans infection, mice lacking TAGAP mount defective immune responses, impaired Th17 cell differentiation, and higher fungal burden. Similarly, in experimental autoimmune encephalomyelitis model of multiple sclerosis, TAGAP deficient mice develop significantly attenuated disease. In summary, we report that TAGAP plays an important role in linking Dectin-induced signaling to the promotion of effective T helper cell immune responses, during both anti-fungal host defense and autoimmunity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-15564-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171161PMC
April 2020

Deficiency of SCAMP5 leads to pediatric epilepsy and dysregulation of neurotransmitter release in the brain.

Hum Genet 2020 Apr 4;139(4):545-555. Epub 2020 Feb 4.

Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, 430074, China.

Secretory carrier membrane proteins (SCAMPs) play an important role in exocytosis in animals, but the precise function of SCAMPs in human disease is unknown. In this study, we identified a homozygous mutation, SCAMP5 R91W, in a Chinese consanguineous family with pediatric epilepsy and juvenile Parkinson's disease. Scamp5 R91W mutant knock-in mice showed typical early-onset epilepsy similar to that in humans. Single-neuron electrophysiological recordings showed that the R91W mutation significantly increased the frequency of miniature excitatory postsynaptic currents (mEPSCs) at a resting state and also increased the amplitude of evoked EPSCs. The R91W mutation affected the interaction between SCAMP5 and synaptotagmin 1 and may affect the function of the SNARE complex, the machinery required for vesicular trafficking and neurotransmitter release. Our work shows that dysfunction of SCAMP5 shifted the excitation/inhibition balance of the neuronal network in the brain, and the deficiency of SCAMP5 leads to pediatric epilepsy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00439-020-02123-9DOI Listing
April 2020

Integrative Analysis of miRNA and mRNA Expression Profiles Associated With Human Atrial Aging.

Front Physiol 2019 19;10:1226. Epub 2019 Sep 19.

Department of Cardiology, The Third Xiangya Hospital of Central South University, Changsha, China.

Background: Limited findings have been reported to systematically study miRNA and mRNA expression profiles in aged human atria. In this study, we aimed to identify miRNAs, genes, and miRNA-mRNA interaction networks for human atrial aging (AA).

Methods: Right atrial appendages from twelve patients who received aortic valve replacement were subjected to miRNA-seq and RNA-seq. All the patients were in sinus rhythm (SR) and stratified by age into four groups. Differential expression analysis was carried out to identify miRNAs and genes for human AA. The miRNA-mRNA interactions for human AA were identified by Pearson correlation analysis and miRNA target prediction programs.

Results: Seven miRNAs (4 upregulation and 3 downregulation) and 42 genes (23 upregulation and 19 downregulation) were differentially expressed in human right atrial tissues between older samples and younger samples. Bioinformatic analysis identified 114 pairs of putative miRNA-mRNA interactions on AA and four types of correlation. Pathway enrichment analysis identified over 40 significant pathways and the top three pathways included rhythmic process ( = 7.5 × 10, = 0.034), senescence and autophagy in cancer ( = 9.0 × 10, = 0.034), and positive regulation of cytokine biosynthetic process ( = 1.1 × 10, = 0.034).

Conclusion: Our study revealed novel miRNA-mRNA interaction networks and signaling pathways for AA, providing novel insights into the development of human AA. Future studies are needed to investigate the potential significance of these miRNA-mRNA interactions in human AA or AA-related cardiovascular diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2019.01226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761282PMC
September 2019

ADAMTS16 activates latent TGF-β, accentuating fibrosis and dysfunction of the pressure-overloaded heart.

Cardiovasc Res 2020 04;116(5):956-969

Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan, PR China.

Aims: Cardiac fibrosis is a major cause of heart failure (HF), and mediated by the differentiation of cardiac fibroblasts into myofibroblasts. However, limited tools are available to block cardiac fibrosis. ADAMTS16 is a member of the ADAMTS superfamily of extracellular protease enzymes involved in extracellular matrix (ECM) degradation and remodelling. In this study, we aimed to establish ADAMTS16 as a key regulator of cardiac fibrosis.

Methods And Results: Western blot and qRT-PCR analyses demonstrated that ADAMTS16 was significantly up-regulated in mice with transverse aortic constriction (TAC) associated with left ventricular hypertrophy and HF, which was correlated with increased expression of Mmp2, Mmp9, Col1a1, and Col3a1. Overexpression of ADAMTS16 accelerated the AngII-induced activation of cardiac fibroblasts into myofibroblasts. Protein structural analysis and co-immunoprecipitation revealed that ADAMTS16 interacted with the latency-associated peptide (LAP)-transforming growth factor (TGF)-β via a RRFR motif. Overexpression of ADAMTS16 induced the activation of TGF-β in cardiac fibroblasts; however, the effects were blocked by a mutation of the RRFR motif to IIFI, knockdown of Adamts16 expression, or a TGF-β-neutralizing antibody (ΝAb). The RRFR tetrapeptide, but not control IIFI peptide, blocked the interaction between ADAMTS16 and LAP-TGF-β, and accelerated the activation of TGF-β in cardiac fibroblasts. In TAC mice, the RRFR tetrapeptide aggravated cardiac fibrosis and hypertrophy by up-regulation of ECM proteins, activation of TGF-β, and increased SMAD2/SMAD3 signalling, however, the effects were blocked by TGF-β-NAb.

Conclusion: ADAMTS16 promotes cardiac fibrosis, cardiac hypertrophy, and HF by facilitating cardiac fibroblasts activation via interacting with and activating LAP-TGF-β signalling. The RRFR motif of ADAMTS16 disrupts the interaction between ADAMTS16 and LAP-TGF-β, activates TGF-β, and aggravated cardiac fibrosis and hypertrophy. This study identifies a novel regulator of TGF-β signalling and cardiac fibrosis, and provides a new target for the development of therapeutic treatment of cardiac fibrosis and HF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cvr/cvz187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868664PMC
April 2020

Angiogenic Factor AGGF1-Primed Endothelial Progenitor Cells Repair Vascular Defect in Diabetic Mice.

Diabetes 2019 08 15;68(8):1635-1648. Epub 2019 May 15.

Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, People's Republic of China

Hyperglycemia-triggered vascular abnormalities are the most serious complications of diabetes mellitus (DM). The major cause of vascular dysfunction in DM is endothelial injury and dysfunction associated with the reduced number and dysfunction of endothelial progenitor cells (EPCs). A major challenge is to identify key regulators of EPCs to restore DM-associated vascular dysfunction. We show that EPCs from heterozygous knockout mice presented with impairment of proliferation, migration, angiogenesis, and transendothelial migration as in hyperglycemic mice fed a high-fat diet (HFD) or mice. The number of EPCs from mice was significantly reduced. Ex vivo, AGGF1 protein can fully reverse all damaging effects of hyperglycemia on EPCs. In vivo, transplantation of AGGF1-primed EPCs successfully restores blood flow and blocks tissue necrosis and ambulatory impairment in HFD-induced hyperglycemic mice or mice with diabetic hindlimb ischemia. Mechanistically, AGGF1 activates AKT, reduces nuclear localization of Fyn, which increases the nuclear level of Nrf2 and expression of antioxidative genes, and inhibits reactive oxygen species generation. These results suggest that is required for essential function of EPCs, AGGF1 fully reverses the damaging effects of hyperglycemia on EPCs, and AGGF1 priming of EPCs is a novel treatment modality for vascular complications in DM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db18-1178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6905488PMC
August 2019

Mutation in causes atrial fibrillation by activating inflammation and cardiac fibrosis in a knock-in rat model.

FASEB J 2019 08 29;33(8):8878-8891. Epub 2019 Apr 29.

Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.

Atrial fibrillation (AF) affects >30 million individuals worldwide. However, no genetic mutation from human patients with AF has been linked to inflammation. Here, we show that AF-associated human variant p.Ile138Thr in natriuretic peptide A () encoding the atrial natriuretic peptide (ANP) causes inflammation, fibroblast activation, atrial fibrosis, and AF in knock-in (KI) rats. Variant p.Ile138Thr inhibits the interaction between ANP and its receptor natriuretic peptide receptor A and reduces intracellular cGMP levels. RNA sequencing and follow-up analyses showed that mutant ANP (mANP) activates multiple innate immunity pathways, including TNF-α, NF-κB, and IL-1β signaling. mANP induces differentiation of cardiac fibroblasts (CFs) to myofibroblasts and promotes CF proliferation and fibrosis. These results suggest that variant p.Ile138Thr causes AF by activating TNF-α, NF-κB, and IL-1β signaling, inflammation, and fibrosis. Multiple computational programs suggest that p.Ile138Thr is damaging or deleterious. Based on the 2015 American College of Medical Genetics and Genomics Standards and Guidelines, p.Ile138Thr can be classified as a likely pathogenic variant. Variant p.Ile138Thr was found only in Asian people in the Genome Aggregation Database and Exome Aggregation Consortium database at an averaged frequency of 0.026%. An estimated 1.15 million Asian people carry the variant and might be at risk of AF. The KI rats may provide an inflammation-based, genetic animal model for AF valuable for testing anti-inflammation or other therapies for AF.-Cheng, C., Liu, H., Tan, C., Tong, D., Zhao, Y., Liu, X., Si, W., Wang, L., Liang, L., Li, J., Wang, C., Chen, Q., Du, Y., Wang, Q. K., Ren, X. Mutation in causes atrial fibrillation by activating inflammation and cardiac fibrosis in a knock-in rat model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1096/fj.201802455RRRDOI Listing
August 2019

Identification of rare variants in cardiac sodium channel β4-subunit gene SCN4B associated with ventricular tachycardia.

Mol Genet Genomics 2019 Aug 17;294(4):1059-1071. Epub 2019 Apr 17.

Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, 430074, People's Republic of China.

Ventricular tachycardia (VT) causes sudden cardiac death, however, the majority of risk genes for VT remain unknown. SCN4B encodes a β-subunit, Naβ4, for the voltage-gated cardiac sodium channel complex involved in generation and conduction of the cardiac action potential. We hypothesized that genomic variants in SCN4B increase the risk of VT. We used high-resolution melt analysis followed by Sanger sequencing to screen 199 VT patients to identify nonsynonymous variants in SCN4B. Two nonsynonymous heterozygous variants in SCN4B were identified in VT patients, including p.Gly8Ser in four VT patients and p.Ala145Ser in one VT patient. Case-control association studies were used to assess the association between variant p.Gly8Ser and VT in two independent populations for VT (299 VT cases vs. 981 controls in population 1 and 270 VT patients vs. 639 controls in population 2). Significant association was identified between p.Gly8Ser and VT in population 1 (P = 1.21 × 10, odds ratio or OR = 11.04), and the finding was confirmed in population 2 (P = 0.03, OR = 3.62). The association remained highly significant in the combined population (P = 3.09 × 10, OR = 6.17). Significant association was also identified between p.Gly8Ser and idiopathic VT (P = 1.89 × 10, OR = 7.27). Functional analysis with Western blotting showed that both p.Gly8Ser and p.Ala145Ser variants significantly reduced the expression level of Naβ4. Based on 2015 ACMG Standards and Guidelines, p.Gly8Ser and p.Ala145Ser can be classified as the pathogenic and likely pathogenic variant, respectively. Our data suggest that SCN4B is a susceptibility gene for common VT and idiopathic VT and link rare SCN4B variants with large effects (OR = 6.17-7.27) to common VT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00438-019-01567-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812521PMC
August 2019

Losartan protects against myocardial ischemia and reperfusion injury vascular integrity preservation.

FASEB J 2019 07 16;33(7):8555-8564. Epub 2019 Apr 16.

Key Laboratory of Molecular Biophysics of the Ministry of Education, Center for Human Genome Research, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.

Vascular hyperpermeability caused by distorted endothelial cell-cell junctions is associated with the no-reflow phenomenon after opening of the occluded vessels in patients with coronary artery disease (CAD), the leading cause of death worldwide. Coronary no-reflow is observed in ∼30% of CAD patients after percutaneous coronary stenting and is associated with a worse prognosis at follow-up and a higher incidence of death. However, limited tools are available to control vascular hyperpermeability and no-reflow. Losartan, an angiotensin II (Ang II) receptor blocker acting on the Ang II type-1 receptor (AT1R) subtype, is a prescription drug for treating hypertension. Here we show that in a murine model of ischemia and reperfusion (I/R), losartan blocked vascular hyperpermeability and decreased infarct size, hemorrhages, edema, and inflammation. Mechanistically, losartan-mediated inhibition of vascular hyperpermeability is mediated by the inhibition of phosphorylation of Src and vascular endothelial cadherin (VE-cadherin), which increases VEGF receptor 2 (VEGFR2)-Src-VE-cadherin complex formation, resulting in increased cell surface VE-cadherin and inhibition of vascular hyperpermeability. On the other hand, hypoxia and reoxygenation increased the phosphorylation levels of Src and VE-cadherin and reduced the formation of the VEGFR2-Src-VE-cadherin complex, which led to reduced cell surface VE-cadherin and increased vascular hyperpermeability; all were inhibited by losartan. These data suggest that losartan may be used for blocking vascular hyperpermeability associated with I/R.-Li, Y., Yao, Y., Li, J., Chen, Q., Zhang, L., Wang, Q. K. Losartan protects against myocardial ischemia and reperfusion injury vascular integrity preservation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1096/fj.201900060RDOI Listing
July 2019

Identification of a p.Trp403* nonsense variant in PHEX causing X-linked hypophosphatemia by inhibiting p38 MAPK signaling.

Hum Mutat 2019 07 28;40(7):879-885. Epub 2019 Mar 28.

Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei, China.

X-linked hypophosphatemia (XLH) is the most common hereditary rickets, caused by mutations in PHEX encoding the phosphate regulating endopeptidase homolog X-linked. Here, we report a nonsense variant in exon 11 of PHEX (c.1209G>A p.Trp403*) cosegregating with XLH in a Chinese family with a LOD score of 2.70. Real-time reverse transcription polymerase chain reaction analysis demonstrated that p.Trp403* variant did not cause nonsense-mediated mRNA decay (NMD), but significantly increased the expression level of FGF23 mRNA in the patients. Interestingly, p.Trp403* significantly reduced phosphorylation of p38 mitogen-activated protein kinase (MAPK) but not ERK1/2. Moreover, overexpression of FGF23 significantly decreased phosphorylation of p38 MAPK, whereas knockdown of FGF23 by siRNA significantly increased phosphorylation of p38 MAPK. These data suggest that p.Trp403* may not function via an NMD mechanism, and instead causes XLH via a novel signaling mechanism involving PHEX, FGF23, and p38 MAPK. This finding provides important insights into genetic and molecular mechanisms for the pathogenesis of XLH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.23743DOI Listing
July 2019

Significant association of rare variant p.Gly8Ser in cardiac sodium channel β4-subunit SCN4B with atrial fibrillation.

Ann Hum Genet 2019 07 1;83(4):239-248. Epub 2019 Mar 1.

Department of Molecular Cardiology, Lerner Research Institute, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio.

Atrial fibrillation (AF) affects 33.5 million individuals worldwide. It accounts for 15% of strokes and increases risk of heart failure and sudden death. The voltage-gated cardiac sodium channel complex is responsible for the generation and conduction of the cardiac action potential, and composed of the main pore-forming α-subunit Na 1.5 (encoded by the SCN5A gene) and one or more auxiliary β-subunits, including Na β1 to Na β4 encoded by SCN1B to SCN4B, respectively. We and others identified loss-of-function mutations in SCN1B and SCN2B and dominant-negative mutations in SCN3B in patients with AF. Three missense variants in SCN4B were identified in sporadic AF patients and small nuclear families; however, the association between SCN4B variants and AF remains to be further defined. In this study, we performed mutational analysis in SCN4B using a panel of 477 AF patients, and identified one nonsynonymous genomic variant p.Gly8Ser in four patients. To assess the association between the p.Gly8Ser variant and AF, we carried out case-control association studies with two independent populations (944 AF patients vs. 9,81 non-AF controls in the first discovery population and 732 cases and 1,291 controls in the second replication population). Significant association was identified in the two independent populations and in the combined population (p = 4.16 × 10 , odds ratio [OR] = 3.14) between p.Gly8Ser and common AF as well as lone AF (p = 0.018, OR = 2.85). These data suggest that rare variant p.Gly8Ser of SCN4B confers a significant risk of AF, and SCN4B is a candidate susceptibility gene for AF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ahg.12305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815221PMC
July 2019

SUMOylation of Vps34 by SUMO1 promotes phenotypic switching of vascular smooth muscle cells by activating autophagy in pulmonary arterial hypertension.

Pulm Pharmacol Ther 2019 04 28;55:38-49. Epub 2019 Jan 28.

Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, PR China; Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA; Department of Molecular Medicine, CCLCM of Case Western Reserve University, Cleveland, OH, 44195, USA; Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA. Electronic address:

Introduction: Pulmonary arterial hypertension (PAH) is a life-threatening disease without effective therapies. PAH is associated with a progressive increase in pulmonary vascular resistance and irreversible pulmonary vascular remodeling. SUMO1 (small ubiquitin-related modifier 1) can bind to target proteins and lead to protein SUMOylation, an important post-translational modification with a key role in many diseases. However, the contribution of SUMO1 to PAH remains to be fully characterized.

Methods: In this study, we explored the role of SUMO1 in the dedifferentiation of vascular smooth muscle cells (VSMCs) involved in hypoxia-induced pulmonary vascular remodeling and PAH in vivo and in vitro.

Results: In a mouse model of hypoxic PAH, SUMO1 expression was significantly increased, which was associated with activation of autophagy (increased LC3b and decreased p62), dedifferentiation of pulmonary arterial VSMCs (reduced α-SMA, SM22 and SM-MHC), and pulmonary vascular remodeling. Similar results were obtained in a MCT-induced PAH model. Overexpression of SUMO1 significantly increased VSMCs proliferation, migration, hypoxia-induced VSMCs dedifferentiation, and autophagy, but these effects were abolished by inhibition of autophagy by 3-MA in aortic VSMCs. Furthermore, SUMO1 knockdown reversed hypoxia-induced proliferation and migration of PASMCs. Mechanistically, SUMO1 promotes Vps34 SUMOylation and the assembly of the Beclin-1-Vps34-Atg14 complex, thereby inducing autophagy, whereas Vps34 mutation K840R reduces Vps34 SUMOylation and inhibits VSMCs dedifferentiation.

Discussion: Our data uncovers an important role of SUMO1 in VSMCs proliferation, migration, autophagy, and phenotypic switching (dedifferentiation) involved in pulmonary vascular remodeling and PAH. Targeting of the SUMO1-Vps34-autophagy signaling axis may be exploited to develop therapeutic strategies to treat PAH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pupt.2019.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814199PMC
April 2019

BCAS2 is essential for hematopoietic stem and progenitor cell maintenance during zebrafish embryogenesis.

Blood 2019 02 27;133(8):805-815. Epub 2018 Nov 27.

Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.

Hematopoietic stem and progenitor cells (HSPCs) originate from the hemogenic endothelium via the endothelial-to-hematopoietic transition, are self-renewing, and replenish all lineages of blood cells throughout life. BCAS2 (breast carcinoma amplified sequence 2) is a component of the spliceosome and is involved in multiple biological processes. However, its role in hematopoiesis remains unknown. We established a knockout zebrafish model by using transcription activator-like effector nucleases. The zebrafish showed severe impairment of HSPCs and their derivatives during definitive hematopoiesis. We also observed significant signs of HSPC apoptosis in the caudal hematopoietic tissue of zebrafish, which may be rescued by suppression of p53. Furthermore, we show that the deletion induces an abnormal alternative splicing of that predisposes cells to undergo p53-mediated apoptosis, which provides a mechanistic explanation of the deficiency observed in HSPCs. Our findings revealed a novel and vital role for BCAS2 during HSPC maintenance in zebrafish.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2018-09-876599DOI Listing
February 2019

Small GTPases SAR1A and SAR1B regulate the trafficking of the cardiac sodium channel Na1.5.

Biochim Biophys Acta Mol Basis Dis 2018 11 6;1864(11):3672-3684. Epub 2018 Sep 6.

Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan 430074, PR China; Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44195, USA. Electronic address:

Background: The cardiac sodium channel Na1.5 is essential for the physiological function of the heart and causes cardiac arrhythmias and sudden death when mutated. Many disease-causing mutations in Na1.5 cause defects in protein trafficking, a cellular process critical to the targeting of Na1.5 to cell surface. However, the molecular mechanisms underlying the trafficking of Na1.5, in particular, the exit from the endoplasmic reticulum (ER) for cell surface trafficking, remain poorly understood.

Methods And Results: Here we investigated the role of the SAR1 GTPases in trafficking of Na1.5. Overexpression of dominant-negative mutant SAR1A (T39N or H79G) or SAR1B (T39N or H79G) significantly reduces the expression level of Na1.5 on cell surface, and decreases the peak sodium current density (I) in HEK/Na1.5 cells and neonatal rat cardiomyocytes. Simultaneous knockdown of SAR1A and SAR1B expression by siRNAs significantly reduces the I density, whereas single knockdown of either SAR1A or SAR1B has minimal effect. Computer modeling showed that the three-dimensional structure of SAR1 is similar to RAN. RAN was reported to interact with MOG1, a small protein involved in regulation of the ER exit of Na1.5. Co-immunoprecipitation showed that SAR1A or SAR1B interacted with MOG1. Interestingly, knockdown of SAR1A and SAR1B expression abolished the MOG1-mediated increases in both cell surface trafficking of Na1.5 and the density of I.

Conclusions: These data suggest that SAR1A and SAR1B are the critical regulators of trafficking of Na1.5. Moreover, SAR1A and SAR1B interact with MOG1, and are required for MOG1-mediated cell surface expression and function of Na1.5.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbadis.2018.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168416PMC
November 2018

phlda3 overexpression impairs specification of hemangioblasts and vascular development.

FEBS J 2018 11 20;285(21):4071-4081. Epub 2018 Sep 20.

Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Cardio-X Institute, Huazhong University of Science and Technology, Wuhan, China.

The phlda3 gene encodes a small, 127-amino acid protein with only a PH domain, and is involved in tumor suppression, proliferation of islet β-cells, insulin secretion, glucose tolerance, and liver injury. However, the role of phlda3 in vascular development is unknown. Here, we show that phlda3 overexpression decreases the expression levels of hemangioblast markers scl, fli1, and etsrp and intersegmental vessel (ISV) markers flk1 and cdh5, and disrupts ISV development in tg(flk1:GFP) and tg(fli1:GFP) zebrafish. Moreover, phlda3 overexpression inhibits the activation of protein kinase B (AKT) in zebrafish embryos, and the developmental defects of ISVs by phlda3 overexpression were reversed by the expression of a constitutively active form of AKT. These data suggest that phlda3 is a negative regulator of hemangioblast specification and ISV development via AKT signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/febs.14653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218282PMC
November 2018

A novel mutation cosegregates with congenital contractural arachnodactyly in a five-generation Chinese family.

Clin Case Rep 2018 Aug 3;6(8):1612-1617. Epub 2018 Jul 3.

Department of Clinical Laboratory Liyuan Hospital Tongji Medical Collage Huazhong University of Science and Technology Wuhan China.

We identified a novel heterozygous mutation (c.4177T>G and p.Cys1393Gly) in that cosegregated with congenital contractural arachnodactyly (CCA) in a five-generation Chinese family. This mutation may cause the loss of the disulfide bond between Cys 1393 and Cys 1378 residues of fibrillin-2. Our study expands the genetic profile of CCA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ccr3.1693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099051PMC
August 2018

Genetic Regulation of the Thymic Stromal Lymphopoietin (TSLP)/TSLP Receptor (TSLPR) Gene Expression and Influence of Epistatic Interactions Between IL-33 and the TSLP/TSLPR Axis on Risk of Coronary Artery Disease.

Front Immunol 2018 3;9:1775. Epub 2018 Aug 3.

Renmin Hospital of Wuhan University, Wuhan, China.

The thymic stromal lymphopoietin (TSLP)/TSLP receptor (TSLPR) axis is involved in multiple inflammatory immune diseases, including coronary artery disease (CAD). To explore the causal relationship between this axis and CAD, we performed a three-stage case-control association analysis with 3,628 CAD cases and 3,776 controls using common variants in the genes (), and . Three common variants in the TSLP/TSLPR axis were significantly associated with CAD in a Chinese Han population [rs3806933 in  = 4.35 × 10, odds ratio (OR) = 1.18; rs6897932 in  = 1.13 × 10, OR = 1.31; g.19646A>G in  = 2.04 × 10, OR = 1.20]. Reporter gene analysis demonstrated that rs3806933 and rs6897932 could influence and expression, respectively. Furthermore, the "T" allele of rs3806933 might increase plasma TSLP levels ( = 0.175,  < 0.01). In a stepwise procedure, the risk for CAD increased by nearly fivefold compared with the maximum effect of any single variant ( = 6.99 × 10, OR = 4.85). In addition, the epistatic interaction between and produced a nearly threefold increase in the risk of CAD in the combined model of rs3806933-rs7025417 ( = 3.67 × 10, OR = 2.98). Our study illustrates that the TSLP/TSLPR axis might be involved in the pathogenesis of CAD through upregulation of mRNA or protein expression of the referenced genes and might have additive effects on the CAD risk when combined with IL-33 signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2018.01775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6085432PMC
September 2019

Analysis of causal effect of APOA5 variants on premature coronary artery disease.

Ann Hum Genet 2018 11 19;82(6):437-447. Epub 2018 Jul 19.

Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.

Apolipoprotein A5 (APOA5) regulates the metabolisms of triglyceride and HDL. APOA5 variants have been linked to coronary artery disease (CAD), but their causal roles are not well studied yet. This study aims to identify the causal effects of APOA5 variants on premature CAD. Sequencing analysis of APOA5 in 128 premature, familiar CAD patients from GeneQuest identified 11 genomic variants, including p.S19W (rs3135506). SKAT analysis showed that all sequenced variants, in aggregate, significantly increased the risk of premature CAD (P-skat = 0.037). Individually, the p.S19W variant was significantly associated with risk of premature CAD (OR = 2.30, P = 0.008) in an independent set of 342 premature CAD patients and 537 controls after adjusting for covariates of sex, age, hypertension, body mass index, triglycerides (TGs), and total, LDL-, and HDL-cholesterol levels. Meanwhile, p.S19W significantly correlated with HDL-C levels (P = 0.048) and TG levels (P = 0.025). Mediation analysis yielded a mediation effect of p.S19W on risk of premature CAD through HDL-C (OR = 0.98, P = 0.040) and TG (OR = 0.98, P = 0.042), suggesting a causal relationship between p.S19W and premature CAD partially through its effects on HDL-C and TG levels. These results suggest that APOA5 variation regulates TG and HDL levels, thus displaying a causal role in the development of CAD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ahg.12273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6188800PMC
November 2018

IL-13 may be involved in the development of CAD via different mechanisms under different conditions in a Chinese Han population.

Sci Rep 2018 04 18;8(1):6182. Epub 2018 Apr 18.

Department of cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.

Interleukin-13 (IL-13) has important functions in atherosclerosis, but its role in coronary artery disease (CAD) is unclear. Here, we studied the genetic role of IL-13 in CAD in a Chinese Han population using tag SNPs covering the whole IL13 gene (i.e., rs1881457, rs2069744 and rs20541) and a two-stage cohort containing 1863 CAD cases and 1841 controls. Traditional risk factors for CAD, such as age, BMI, and other factors, were used as covariates in logistic regression analysis. In the total population, we found that two haplotypes of IL13 (ATG and ATA, ordered rs1881457-rs2069744-rs20541) significantly contributed to the risk of CAD with adjusted p values less than 0.05 (p = 0.019 and p = 0.042, respectively). In subgroup population analyses, the variant rs1881457 was found to significantly contribute to a nearly two fold increase in the risk of CAD in men (p = 0.023, OR = 1.91, 95% CI: 1.09-3.33). The variant rs1881457 also significantly contributed to a nearly twofold risk of late-onset CAD (p = 0.024, OR = 1.93, 95% CI: 1.09-3.42). In conclusion, IL13 might be involved in CAD via different mechanisms under different conditions in the Chinese Han population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-24592-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906444PMC
April 2018

Significant Association between OPG/TNFRSF11B Variant and Common Complex Ischemic Stroke.

J Stroke Cerebrovasc Dis 2018 Jun 28;27(6):1683-1691. Epub 2018 Feb 28.

Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China; Center for Cardiovascular Genetics, Cleveland Clinic, Cleveland, Ohio; Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio; Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio. Electronic address:

Background: The serum level of osteoprotegerin (encoded by OPG or TNFRSF11B) was previously shown to be increased in patients with ischemic stroke. A single nucleotide polymorphism rs3134069 in the TNFRSF11B gene was previously associated with ischemic stroke in a population of diabetic patients in Italy. It remains to be determined whether rs3134069 is associated with ischemic stroke in the general population or populations without diabetes.

Materials And Methods: We genotyped rs3134069 and performed a case-control association study to test whether rs3134069 is associated with ischemic stroke in 2 independent Chinese Han populations, including a China-Central population with 1629 cases and 1504 controls and a China-Northern population with 1206 cases and 720 controls.

Results: rs3134069 showed significant association with ischemic stroke in the China-Central population (P = 9.24 × 10, odds ratio [OR] = 1.50). The association was replicated in the independent China-Northern population (P = 2.45 × 10, OR = 1.53). The association became more significant in the combined population (P = 7.09 × 10, OR = 1.41). The associations remained significant in the male population, female population, and population without type 2 diabetes. Our expression quantitative trait loci analysis found that the minor allele C of rs3134069 was significantly associated with a decreasedexpression level of TNFRSF11B (P = .002).

Conclusions: This study demonstrates that rs3134069 in TNFRSF11B increases risk of ischemic stroke by decreasing TNFRSF11B expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2018.01.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815228PMC
June 2018

Genomic Variants in NEURL, GJA1 and CUX2 Significantly Increase Genetic Susceptibility to Atrial Fibrillation.

Sci Rep 2018 02 19;8(1):3297. Epub 2018 Feb 19.

Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, P.R. China.

Atrial fibrillation (AF) is the most common arrhythmia. In 2014, two new meta-GWAS identified 5 AF loci, including the NEURL locus, GJA1 locus, CAND2 locus, and TBX5 locus in the European ancestry populations and the NEURL locus and CUX2 locus in a Japanese population. The TBX5 locus for AF was reported by us in 2013 in the Chinese population. Here we assessed the association between AF and SNPs in the NEURL, GJA1, CAND2 and CUX2 loci in the Chinese Han population. We carried out a large case-control association study with 1,164 AF patients and 1,460 controls. Significant allelic and genotypic associations were identified between NEURL variant rs6584555 and GJA1 variant rs13216675 and AF. Significant genotypic association was found between CUX2 SNP rs6490029 and AF. No association was found between CAND2 variant rs4642101 and AF, which may be due to an insufficient power of the sample size for rs4642101. Together with our previous findings, seven of fifteen AF loci (<50%) identified by GWAS in the European ancestry populations conferred susceptibility to AF in the Chinese population, and explained approximately 14.5% of AF heritability. On the other hand, two AF loci identified in the Japanese population were both replicated in the Chinese population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-21611-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5818533PMC
February 2018

Identification of a mutation in CNNM4 by whole exome sequencing in an Amish family and functional link between CNNM4 and IQCB1.

Mol Genet Genomics 2018 Jun 10;293(3):699-710. Epub 2018 Jan 10.

Center for Genetic Eye Diseases, Cleveland Clinic Cole Eye Institute, Cleveland, OH, 44195, USA.

We investigated an Amish family in which three siblings presented with an early-onset childhood retinal dystrophy inherited in an autosomal recessive fashion. Genome-wide linkage analysis identified significant linkage to marker D2S2216 on 2q11 with a two-point LOD score of 1.95 and a multi-point LOD score of 3.76. Whole exome sequencing was then performed for the three affected individuals and identified a homozygous nonsense mutation (c.C1813T, p.R605X) in the cyclin and CBS domain divalent metal cation transport mediator 4 (CNNM4) gene located within the 2p14-2q14 Jalili syndrome locus. The initial assessment and collection of the family were performed before the clinical delineation of Jalili syndrome. Another assessment was made after the discovery of the responsible gene and the dental abnormalities characteristic of Jalili syndrome were retrospectively identified. The p.R605X mutation represents the first probable founder mutation of Jalili syndrome identified in the Amish community. The molecular mechanism underlying Jalili syndrome is unknown. Here we show that CNNM4 interacts with IQCB1, which causes Leber congenital amaurosis (LCA) when mutated. A truncated CNNM4 protein starting at R605 significantly increased the rate of apoptosis, and significantly increased the interaction between CNNM4 and IQCB1. Mutation p.R605X may cause Jalili syndrome by a nonsense-mediated decay mechanism, affecting the function of IQCB1 and apoptosis, or both. Our data, for the first time, functionally link Jalili syndrome gene CNNM4 to LCA gene IQCB1, providing important insights into the molecular pathogenic mechanism of retinal dystrophy in Jalili syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00438-018-1417-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5949075PMC
June 2018

Lack of association between the variant rs9943582 with ischemic stroke in the Chinese Han GeneID population.

Oncotarget 2017 Dec 21;8(64):107678-107684. Epub 2017 Nov 21.

Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Human Genome Research Center, Huazhong University of Science and Technology, Wuhan, P.R. China.

Stroke is one of the most common causes of death worldwide. Genetic risk factors have been found to play important roles in the pathology of ischemic stroke. In a previous genome-wide association study, a functional variant (rs9943582, -154G/A) in the 5' flanking region of the apelin receptor gene () was shown to be significantly associated with stroke in the Japanese population. However, the association required validation in other ethnicities. To validate the genetic relationship between and ischemic stroke in the Chinese Han population, we genotyped rs9943582 in a case-control population containing 1,158 ischemic stroke patients and 1,265 common controls enrolled from the GeneID database, and performed a genetic association study. We detected no allelic or genotypic associations between rs9943582 and ischemic stroke in the Chinese Han GeneID population, although the study population provided sufficient statistical power. This finding indicates that the association between the variant and ischemic stroke or atherosclerosis may need further validation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.22588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5746099PMC
December 2017

Significant genetic association of a functional TFPI variant with circulating fibrinogen levels and coronary artery disease.

Mol Genet Genomics 2018 Feb 11;293(1):119-128. Epub 2017 Sep 11.

Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.

The tissue factor pathway inhibitor (TFPI) gene encodes a protease inhibitor with a critical role in regulation of blood coagulation. Some genomic variants in TFPI were previously associated with plasma TFPI levels, however, it remains to be further determined whether TFPI variants are associated with other coagulation factors. In this study, we carried out a large population-based study with 2313 study subjects for blood coagulation data, including fibrinogen levels, prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin time (TT). We identified significant association of TFPI variant rs10931292 (a functional promoter variant with reduced transactivation) with increased plasma fibrinogen levels (P = 0.017 under a recessive model), but not with PT, APTT or TT (P > 0.05). Using a large case-control association study population with 4479 CAD patients and 3628 controls, we identified significant association between rs10931292 and CAD under a recessive model (OR 1.23, P = 0.005). For the first time, we show that a TFPI variant is significantly associated with fibrinogen levels and risk of CAD. Our finding contributes significantly to the elucidation of the genetic basis and biological pathways responsible for fibrinogen levels and development of CAD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00438-017-1365-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794607PMC
February 2018

A non-canonical pathway regulates ER stress signaling and blocks ER stress-induced apoptosis and heart failure.

Nat Commun 2017 07 25;8(1):133. Epub 2017 Jul 25.

Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430074, China.

Endoplasmic reticulum stress is an evolutionarily conserved cell stress response associated with numerous diseases, including cardiac hypertrophy and heart failure. The major endoplasmic reticulum stress signaling pathway causing cardiac hypertrophy involves endoplasmic reticulum stress sensor PERK (protein kinase-like kinase) and eIF2α-ATF4-CHOP signaling. Here, we describe a non-canonical, AGGF1-mediated regulatory system for endoplasmic reticulum stress signaling associated with increased p-eIF2α and ATF4 and decreased sXBP1 and CHOP. Specifically, we see a reduced AGGF1 level consistently associated with induction of endoplasmic reticulum stress signaling in mouse models and human patients with heart failure. Mechanistically, AGGF1 regulates endoplasmic reticulum stress signaling by inhibiting ERK1/2 activation, which reduces the level of transcriptional repressor ZEB1, leading to induced expression of miR-183-5p. miR-183-5p post-transcriptionally downregulates CHOP and inhibits endoplasmic reticulum stress-induced apoptosis. AGGF1 protein therapy and miR-183-5p regulate endoplasmic reticulum stress signaling and block endoplasmic reticulum stress-induced apoptosis, cardiac hypertrophy, and heart failure, providing an attractive paradigm for treatment of cardiac hypertrophy and heart failure.Endoplasmic reticulum (ER) stress promotes cardiac dysfunction. Here the authors uncover a pathway whereby AGGF1 blocks ER stress by inhibiting ERK1/2 activation and the transcriptional repressor ZEB1, leading to induction of miR-183-5p and down-regulation of CHOP, and show that AGGF1 can effectively treat cardiac hypertrophy and heart failure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-017-00171-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5527107PMC
July 2017

Genome-Wide Linkage Analysis of Large Multiple Multigenerational Families Identifies Novel Genetic Loci for Coronary Artery Disease.

Sci Rep 2017 07 14;7(1):5472. Epub 2017 Jul 14.

Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.

Coronary artery disease (CAD) is the leading cause of death, and genetic factors contribute significantly to risk of CAD. This study aims to identify new CAD genetic loci through a large-scale linkage analysis of 24 large and multigenerational families with 433 family members (GeneQuest II). All family members were genotyped with markers spaced by every 10 cM and a model-free nonparametric linkage (NPL-all) analysis was carried out. Two highly significant CAD loci were identified on chromosome 17q21.2 (NPL score of 6.20) and 7p22.2 (NPL score of 5.19). We also identified four loci with significant NPL scores between 4.09 and 4.99 on 2q33.3, 3q29, 5q13.2 and 9q22.33. Similar analyses in individual families confirmed the six significant CAD loci and identified seven new highly significant linkages on 9p24.2, 9q34.2, 12q13.13, 15q26.1, 17q22, 20p12.3, and 22q12.1, and two significant loci on 2q11.2 and 11q14.1. Two loci on 3q29 and 9q22.33 were also successfully replicated in our previous linkage analysis of 428 nuclear families. Moreover, two published risk variants, SNP rs46522 in UBE2Z and SNP rs6725887 in WDR12 by GWAS, were found within the 17q21.2 and 2q33.3 loci. These studies lay a foundation for future identification of causative variants and genes for CAD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-017-05381-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5511258PMC
July 2017

NINJ2- A novel regulator of endothelial inflammation and activation.

Cell Signal 2017 07 18;35:231-241. Epub 2017 Apr 18.

Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Human Genome Research Center, Huazhong University of Science and Technology, Wuhan 430074, PR China. Electronic address:

Previous genetic studies suggested that variants in NINJ2 (encode ninjurin2) confer risk to ischemic stroke or large artery atherosclerotic stroke. However, the underlying mechanisms of NINJ2 in ischemic stroke or atherosclerosis are still unknown. In this study, we hypothesized that NINJ2 may play a role in endothelial inflammation and activation, and regulate the process of atherosclerosis. Here, we demonstrated that NINJ2 can regulate the expression of a panel of genes that are associated with inflammation and atherosclerosis (e.g. IL-1β, TNF-α, IL-8, IL-6, ICAM-1 and E-selectin) in human vascular endothelial cells (HUVECs). Moreover, we found the expression of ninjurin2 is upregulated in LPS stimulated HUVECs and mouse aorta, and it can regulate LPS-induced endothelial activation and the adhesion of monocytes to endothelial cells. We also found that NINJ2 can regulate NF-κB and c-jun through interacting with TLR4. In conclusion, our study suggests that ninjurin2 is a novel regulator of endothelia inflammation and activation through TLR4 signaling pathways, and these data provided new insights into the mechanisms between NINJ2 and atherosclerosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cellsig.2017.04.011DOI Listing
July 2017

Genome-Wide Analysis of DNA Methylation and Acute Coronary Syndrome.

Circ Res 2017 May 27;120(11):1754-1767. Epub 2017 Mar 27.

From the Key Laboratory of Environment and Health, Ministry of Education and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China (J.L., X. Zhu, K.Y., H.J., Y.Z., S.D., X. Liu, X. Zhang, M.H., W.C., J.Y., Y.B., X. Han, B.L., X. He, H.S., C.L., Y.G., B.Z., Z.Z., A.P., Y.Y., F.A., T.W.); Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA (J.L., L.Q., F.B.H.); Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China (L.C., Q.Z., X.M., Y.P., Y.M.); Environmental Health Science, Columbia University Mailman School of Public Health, New York, NY (J.Z.); Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China (M.G., B.M., F.Z.); Department of Cardiology, People's Hospital of Zhuhai, Guangdong, China (X. Luo, W.M.); Department of Cardiology, Bao'an Hospital, Shenzhen, Guangdong, China (S.S.); Department of Cardiology, Wuhan Central Hospital, Wuhan, Hubei, China (L.Z., P.H.); Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China (H.Z.); Departments of Epidemiology and Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA (J.H., L.L.); and Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei, China (Q.K.W.).

Rationale: Acute coronary syndrome (ACS) is a leading cause of death worldwide. Immune functions play a vital role in ACS development; however, whether epigenetic modulation contributes to the regulation of blood immune cells in this disease has not been investigated.

Objective: We conducted an epigenome-wide analysis with circulating immune cells to identify differentially methylated genes in ACS.

Methods And Results: We examined genome-wide methylation of whole blood in 102 ACS patients and 101 controls using HumanMethylation450 array, and externally replicated significant discoveries in 100 patients and 102 controls. For the replicated loci, we further analyzed their association with ACS in 6 purified leukocyte subsets, their correlation with the expressions of annotated genes, and their association with cardiovascular traits/risk factors. We found novel and reproducible association of ACS with blood methylation at 47 cytosine-phosphoguanine sites (discovery: false discovery rate <0.005; replication: Bonferroni corrected <0.05). The association of methylation levels at these cytosine-phosphoguanine sites with ACS was further validated in at least 1 of the 6 leukocyte subsets, with predominant contributions from CD8 T cells, CD4 T cells, and B cells. Blood methylation of 26 replicated cytosine-phosphoguanine sites showed significant correlation with expressions of annotated genes (including , , and ; <5.9×10), and differential gene expression in case versus controls corroborated the observed differential methylation. The replicated loci suggested a role in ACS-relevant functions including chemotaxis, coronary thrombosis, and T-cell-mediated cytotoxicity. Functional analysis using the top ACS-associated methylation loci in purified T and B cells revealed vital pathways related to atherogenic signaling and adaptive immune response. Furthermore, we observed a significant enrichment of the replicated cytosine-phosphoguanine sites associated with smoking and low-density lipoprotein cholesterol (≤1×10).

Conclusions: Our study identified novel blood methylation alterations associated with ACS and provided potential clinical biomarkers and therapeutic targets. Our results may suggest that immune signaling and cellular functions might be regulated at an epigenetic level in ACS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCRESAHA.116.310324DOI Listing
May 2017
-->