The Experts below are selected from a list of 1212 Experts worldwide ranked by ideXlab platform
You-yang Zhao - One of the best experts on this subject based on the ideXlab platform.
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Endothelial Autocrine Signaling through CXCL12/CXCR4/FoxM1 Axis Contributes to Severe Pulmonary Arterial Hypertension
International journal of molecular sciences, 2021Co-Authors: Bin Liu, Ting Wang, Qi Liao, Maggie M. Zhu, You-yang Zhao, Zhiyu DaiAbstract:Endothelial autocrine signaling is essential to maintain vascular homeostasis. There is limited information about the role of endothelial autocrine signaling in regulating severe pulmonary vascular remodeling during the onset of pulmonary arterial hypertension (PAH). In this study, we employed the first severe pulmonary hypertension (PH) mouse model, EGLN1Tie2Cre (Tie2Cre-mediated disruption of EGLN1) mice, to identify the novel autocrine signaling mediating the pulmonary vascular endothelial cell (PVEC) proliferation and the pathogenesis of PAH. PVECs isolated from EGLN1Tie2Cre lung expressed upregulation of many growth factors or angiocrine factors such as CXCL12, and exhibited pro-proliferative phenotype coincident with the upregulation of proliferation-specific transcriptional factor FoxM1. Treatment of CXCL12 on PVECs increased FoxM1 expression, which was blocked by CXCL12 receptor CXCR4 antagonist AMD3100 in cultured human PVECs. The endothelial specific deletion of Cxcl12(EGLN1/Cxcl12Tie2Cre) or AMD3100 treatment in EGLN1Tie2Cre mice downregulated FoxM1 expression in vivo. We then generated and characterized a novel mouse model with endothelial specific FoxM1 deletion in EGLN1Tie2Cremice (EGLN1/Foxm1Tie2Cre), and found that endothelial FoxM1 deletion reduced pulmonary vascular remodeling and right ventricular systolic pressure. Together, our study identified a novel mechanism of endothelial autocrine signaling in regulating PVEC proliferation and pulmonary vascular remodeling in PAH.
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Endothelial Autocrine Signaling through 2CXCL12/CXCR4/FoxM1 Axis Contributes to Severe Pulmonary Arterial Hypertension
2021Co-Authors: Bin Liu, Ting Wang, Qi Liao, Maggie M. Zhu, You-yang Zhao, Zhiyu DaiAbstract:Endothelial autocrine signaling is essential to maintain vascular hemostasis. There is limited in-formation about the role of endothelial autocrine signaling in regulating severe pulmonary vas-cular remodeling during the onset of pulmonary arterial hypertension (PAH). In this study, we employed the first severe PAH mouse model, EGLN1Tie2Cre (Tie2Cre-mediated disruption of EGLN1) mice, to identify the novel autocrine signaling mediating the pulmonary vascular endothelial cells (PVECs) hyperproliferation and the pathogenesis of PAH. PVECs isolated from EGLN1Tie2Cre lung expressed upregulation of many growth factors or angiocrine factors such as CXCL12, and exhib-ited hyperproliferative phenotype in coincident with upregulation of proliferation specific tran-scriptional factor FoxM1. Treatment of CXCL12 on PVECs increased FoxM1 expression, which was blocked by CXCL12 receptor CXCR4 antagonist AMD3100 in culture human PVECs. Endo-thelial specific deletion of Cxcl12 (EGLN1/Cxcl12Tie2 Cre) or AMD3100 treatment in EGLN1Tie2Cre mice downregulated FoxM1 expression in vivo. We then generated and characterized a novel mouse model with endothelial specific FoxM1 deletion in EGLN1Tie2Cre mice (EGLN1/Foxm1Tie2Cre), and found that endothelial FoxM1 deletion reduced pulmonary vascular remodeling and right ventricular systolic pressure. Together, our study identified a novel mechanism of endothelial autocrine sig-naling in regulating PVECs hyperproliferation and pulmonary vascular remodeling in PAH.
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Endothelial Autocrine Signaling Contributes to Severe Pulmonary Arterial Hypertension
2021Co-Authors: Bin Liu, Ting Wang, Qi Liao, Maggie M. Zhu, You-yang Zhao, Zhiyu DaiAbstract:Endothelial autocrine signaling is essential to maintain vascular hemostasis. There is limited in-formation about the role of endothelial autocrine signaling in regulating severe pulmonary vas-cular remodeling during the onset of pulmonary arterial hypertension (PAH). In this study, we employed the first severe PAH mouse model, EGLN1Tie2Cre (Tie2Cre-mediated disruption of EGLN1) mice, to identify the novel autocrine signaling mediating the pulmonary vascular endothelial cells (PVECs) hyperproliferation and the pathogenesis of PAH. PVECs isolated from EGLN1Tie2Cre lung expressed upregulation of many growth factors or angiocrine factors such as CXCL12, and exhib-ited hyperproliferative phenotype in coincident with upregulation of proliferation specific tran-scriptional factor FoxM1. Treatment of CXCL12 on PVECs increased FoxM1 expression, which was blocked by CXCL12 receptor CXCR4 antagonist AMD3100 in culture human PVECs. Endo-thelial specific deletion of Cxcl12 (EGLN1/Cxcl12Tie2 Cre) or AMD3100 treatment in EGLN1Tie2Cre mice downregulated FoxM1 expression in vivo. We then generated and characterized a novel mouse model with endothelial specific FoxM1 deletion in EGLN1Tie2Cre mice (EGLN1/Foxm1Tie2Cre), and found that endothelial FoxM1 deletion reduced pulmonary vascular remodeling and right ventricular systolic pressure. Together, our study identified a novel mechanism of endothelial autocrine sig-naling in regulating PVECs hyperproliferation and pulmonary vascular remodeling in PAH.
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Endothelial and Smooth Muscle Cell Interaction via FoxM1 Signaling Mediates Vascular Remodeling and Pulmonary Hypertension
American journal of respiratory and critical care medicine, 2018Co-Authors: Zhiyu Dai, Maggie M. Zhu, Xianming Zhang, Yi Peng, Hua Jin, Narsa Machireddy, Zhijian Qian, You-yang ZhaoAbstract:Rationale: Angioproliferative vasculopathy is a hallmark of pulmonary arterial hypertension (PAH). However, little is known about how endothelial cell (EC) and smooth muscle cell (SMC) crosstalk regulates the angioproliferative vascular remodeling.Objectives: To investigate the role of EC and SMC interaction and underlying signaling pathways in pulmonary hypertension (PH) development.Methods: SMC-specific Foxm1 (forkhead box M1) or Cxcr4 knockout mice, EC-specific Foxm1 or EGLN1 knockout mice, and EC-specific EGLN1/Cxcl12 double knockout mice were used to assess the role of FoxM1 on SMC proliferation and PH. Lung tissues and cells from patients with PAH were used to validate clinical relevance. FoxM1 inhibitor thiostrepton was used in Sugen 5416/hypoxia- and monocrotaline-challenged rats.Measurements and Main Results: FoxM1 expression was markedly upregulated in lungs and pulmonary arterial SMCs of patients with idiopathic PAH and four discrete PH rodent models. Mice with SMC- (but not EC-) specific delet...
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Abstract 12629: Endothelial Prolyl-4 hydroxylase 2 Deletion Induces Cardiac Hypertrophy and Heart Failure via Hypoxia Inducible Factor-2α Activation
Circulation, 2016Co-Authors: Zhiyu Dai, Maggie M. Zhu, Chen Gao, Xianming Zhang, You-yang ZhaoAbstract:Background: Cardiac hypertrophy is a common adaptive response to injury and stress, and can eventually lead to heart failure. The role of endothelial Prolyl-4 hydroxylase 2 (PHD2)/hypoxia inducible factors (HIFs) signaling in the pathogenesis of heart failure is unclear. We hypothesize that endothelial PHD2/HIF signaling dysfunction contributes to cardiac hypertrophy and heart failure. Methods: Mice with Tie2-Cre-mediated deletion of EGLN1 (encoding PHD2) ( EGLN1 Tie2-Cre ), as well as double knockout mice with both EGLN1 and Hif1a or EGLN1 and Hif2a were generated. EGLN1 f/f bone marrow cells were transplanted to lethally irradiated EGLN1 Tie2-Cre mice to determine the contribution of bone marrow cells in cardiac hypertrophy. Mice carrying EGLN1 f/f were bred into Endo SCL- Cre- ER(T) mice containing tamoxifen-inducible Cre to generate mice with EGLN1 deletion only in endothelial cells in adult mice ( EGLN1 SCL-Cre ) after tamoxifen injection. Echocardiography were measured to study cardiac size and function. Histological examination was also performed. Results: EGLN1 Tie2-Cre mice exhibited left ventricular hypertrophy evident by increased thickness of anterior and posterior wall and left ventricular mass, as well as cardiac fibrosis. EGLN1 deletion in bone marrow cells did not contribute to cardiac hypertrophy. Tamoxifen induced endothelial EGLN1 deletion in adult EGLN1 SCL-Cre mice also induced left ventricular hypertrophy and heart failure. Genetic ablation of Hif2a but not Hif1a in EGLN1 Tie2 mice normalized cardiac size and function. Additionally, we observed a marked decrease of PHD2 expression in heart tissues from patients with dilated cardiomyopathy. Conclusion: This studies define for the first time an unexpected role of endothelial PHD2 deficiency in inducing cardiac hypertrophy and heart failure in a HIF-2α dependent manner. Thus, targeting PHD2/HIF-2α signaling represents a novel therapeutic approach for the treatment of heart failure.
Yiqun Jiang - One of the best experts on this subject based on the ideXlab platform.
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EGLN1/c-Myc Induced Lymphoid-Specific Helicase Inhibits Ferroptosis through Lipid Metabolic Gene Expression Changes
Theranostics, 2017Co-Authors: Yiqun Jiang, Chao Mao, Rui Yang, Bin Yan, Ying Shi, Xiaoli Liu, Weiwei Lai, Yating Liu, Xiang Wang, Desheng XiaoAbstract:Ferroptosis is a newly discovered form of non-apoptotic cell death in multiple human diseases. However, the epigenetic mechanisms underlying ferroptosis remain poorly defined. First, we demonstrated that lymphoid-specific helicase (LSH), which is a DNA methylation modifier, interacted with WDR76 to inhibit ferroptosis by activating lipid metabolism-associated genes, including GLUT1, and ferroptosis related genes SCD1 and FADS2, in turn, involved in the Warburg effect. WDR76 targeted these genes expression in dependent manner of LSH and chromatin modification in DNA methylation and histone modification. These effects were dependent on iron and lipid reactive oxygen species. We further demonstrated that EGLN1 and c-Myc directly activated the expression of LSH by inhibiting HIF-1α. Finally, we demonstrated that LSH functioned as an oncogene in lung cancer in vitro and in vivo. Therefore, our study elucidates the molecular basis of the c-Myc/EGLN1-mediated induction of LSH expression that inhibits ferroptosis, which can be exploited for the development of therapeutic strategies targeting ferroptosis for the treatment of cancer.
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EGLN1 c myc induced lymphoid specific helicase inhibits ferroptosis through lipid metabolic gene expression changes
Theranostics, 2017Co-Authors: Yiqun Jiang, Chao Mao, Rui Yang, Bin Yan, Ying Shi, Xiaoli Liu, Weiwei Lai, Yating Liu, Xiang Wang, Desheng XiaoAbstract:Ferroptosis is a newly discovered form of non-apoptotic cell death in multiple human diseases. However, the epigenetic mechanisms underlying ferroptosis remain poorly defined. First, we demonstrated that lymphoid-specific helicase (LSH), which is a DNA methylation modifier, interacted with WDR76 to inhibit ferroptosis by activating lipid metabolism-associated genes, including GLUT1, and ferroptosis related genes SCD1 and FADS2, in turn, involved in the Warburg effect. WDR76 targeted these genes expression in dependent manner of LSH and chromatin modification in DNA methylation and histone modification. These effects were dependent on iron and lipid reactive oxygen species. We further demonstrated that EGLN1 and c-Myc directly activated the expression of LSH by inhibiting HIF-1α. Finally, we demonstrated that LSH functioned as an oncogene in lung cancer in vitro and in vivo. Therefore, our study elucidates the molecular basis of the c-Myc/EGLN1-mediated induction of LSH expression that inhibits ferroptosis, which can be exploited for the development of therapeutic strategies targeting ferroptosis for the treatment of cancer.
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Abstract 4317: EGLN1/c-Myc induced lymphoid-specific helicase inhibits ferroptosis through lipid metabolic gene expression changes
Molecular and Cellular Biology Genetics, 2017Co-Authors: Yongguang Tao, Shuang Liu, Yiqun JiangAbstract:Ferroptosis has emerged as a new form of non-apoptotic cell death in multiple human diseases. However, the epigenetic mechanisms of ferroptosis remain poorly defined. We demonstrate that Lymphoid-specific helicase (LSH), a DNA methylation modifier, interacts with WDR76 to inhibit ferroptosis by activating lipid metabolism-associated genes, including GLUT1, and ferroptosis related genes SCD1 and FADS2. These effects are dependent on iron and lipid reactive oxygen species. We further show that EGLN1 and c-Myc directly activate LSH expression by inhibiting HIF-1α. Finally, we demonstrate that LSH functions as an oncogene in lung cancer in vitro and in vivo. Therefore, our study elucidates the molecular basis for a c-Myc/EGLN1-mediated induction of LSH expression to inhibit ferroptosis, which can be exploited for the development of therapeutic agents to target ferroptosis in cancer. Note: This abstract was not presented at the meeting. Citation Format: Yongguang Tao, Shuang Liu, Yiqun Jiang. EGLN1/c-Myc induced lymphoid-specific helicase inhibits ferroptosis through lipid metabolic gene expression changes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4317. doi:10.1158/1538-7445.AM2017-4317
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abstract 4317 EGLN1 c myc induced lymphoid specific helicase inhibits ferroptosis through lipid metabolic gene expression changes
Cancer Research, 2017Co-Authors: Yongguang Tao, Shuang Liu, Yiqun JiangAbstract:Ferroptosis has emerged as a new form of non-apoptotic cell death in multiple human diseases. However, the epigenetic mechanisms of ferroptosis remain poorly defined. We demonstrate that Lymphoid-specific helicase (LSH), a DNA methylation modifier, interacts with WDR76 to inhibit ferroptosis by activating lipid metabolism-associated genes, including GLUT1, and ferroptosis related genes SCD1 and FADS2. These effects are dependent on iron and lipid reactive oxygen species. We further show that EGLN1 and c-Myc directly activate LSH expression by inhibiting HIF-1α. Finally, we demonstrate that LSH functions as an oncogene in lung cancer in vitro and in vivo. Therefore, our study elucidates the molecular basis for a c-Myc/EGLN1-mediated induction of LSH expression to inhibit ferroptosis, which can be exploited for the development of therapeutic agents to target ferroptosis in cancer. Note: This abstract was not presented at the meeting. Citation Format: Yongguang Tao, Shuang Liu, Yiqun Jiang. EGLN1/c-Myc induced lymphoid-specific helicase inhibits ferroptosis through lipid metabolic gene expression changes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4317. doi:10.1158/1538-7445.AM2017-4317
Zhiyu Dai - One of the best experts on this subject based on the ideXlab platform.
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Endothelial Autocrine Signaling through CXCL12/CXCR4/FoxM1 Axis Contributes to Severe Pulmonary Arterial Hypertension
International journal of molecular sciences, 2021Co-Authors: Bin Liu, Ting Wang, Qi Liao, Maggie M. Zhu, You-yang Zhao, Zhiyu DaiAbstract:Endothelial autocrine signaling is essential to maintain vascular homeostasis. There is limited information about the role of endothelial autocrine signaling in regulating severe pulmonary vascular remodeling during the onset of pulmonary arterial hypertension (PAH). In this study, we employed the first severe pulmonary hypertension (PH) mouse model, EGLN1Tie2Cre (Tie2Cre-mediated disruption of EGLN1) mice, to identify the novel autocrine signaling mediating the pulmonary vascular endothelial cell (PVEC) proliferation and the pathogenesis of PAH. PVECs isolated from EGLN1Tie2Cre lung expressed upregulation of many growth factors or angiocrine factors such as CXCL12, and exhibited pro-proliferative phenotype coincident with the upregulation of proliferation-specific transcriptional factor FoxM1. Treatment of CXCL12 on PVECs increased FoxM1 expression, which was blocked by CXCL12 receptor CXCR4 antagonist AMD3100 in cultured human PVECs. The endothelial specific deletion of Cxcl12(EGLN1/Cxcl12Tie2Cre) or AMD3100 treatment in EGLN1Tie2Cre mice downregulated FoxM1 expression in vivo. We then generated and characterized a novel mouse model with endothelial specific FoxM1 deletion in EGLN1Tie2Cremice (EGLN1/Foxm1Tie2Cre), and found that endothelial FoxM1 deletion reduced pulmonary vascular remodeling and right ventricular systolic pressure. Together, our study identified a novel mechanism of endothelial autocrine signaling in regulating PVEC proliferation and pulmonary vascular remodeling in PAH.
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Endothelial Autocrine Signaling through 2CXCL12/CXCR4/FoxM1 Axis Contributes to Severe Pulmonary Arterial Hypertension
2021Co-Authors: Bin Liu, Ting Wang, Qi Liao, Maggie M. Zhu, You-yang Zhao, Zhiyu DaiAbstract:Endothelial autocrine signaling is essential to maintain vascular hemostasis. There is limited in-formation about the role of endothelial autocrine signaling in regulating severe pulmonary vas-cular remodeling during the onset of pulmonary arterial hypertension (PAH). In this study, we employed the first severe PAH mouse model, EGLN1Tie2Cre (Tie2Cre-mediated disruption of EGLN1) mice, to identify the novel autocrine signaling mediating the pulmonary vascular endothelial cells (PVECs) hyperproliferation and the pathogenesis of PAH. PVECs isolated from EGLN1Tie2Cre lung expressed upregulation of many growth factors or angiocrine factors such as CXCL12, and exhib-ited hyperproliferative phenotype in coincident with upregulation of proliferation specific tran-scriptional factor FoxM1. Treatment of CXCL12 on PVECs increased FoxM1 expression, which was blocked by CXCL12 receptor CXCR4 antagonist AMD3100 in culture human PVECs. Endo-thelial specific deletion of Cxcl12 (EGLN1/Cxcl12Tie2 Cre) or AMD3100 treatment in EGLN1Tie2Cre mice downregulated FoxM1 expression in vivo. We then generated and characterized a novel mouse model with endothelial specific FoxM1 deletion in EGLN1Tie2Cre mice (EGLN1/Foxm1Tie2Cre), and found that endothelial FoxM1 deletion reduced pulmonary vascular remodeling and right ventricular systolic pressure. Together, our study identified a novel mechanism of endothelial autocrine sig-naling in regulating PVECs hyperproliferation and pulmonary vascular remodeling in PAH.
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Endothelial Autocrine Signaling Contributes to Severe Pulmonary Arterial Hypertension
2021Co-Authors: Bin Liu, Ting Wang, Qi Liao, Maggie M. Zhu, You-yang Zhao, Zhiyu DaiAbstract:Endothelial autocrine signaling is essential to maintain vascular hemostasis. There is limited in-formation about the role of endothelial autocrine signaling in regulating severe pulmonary vas-cular remodeling during the onset of pulmonary arterial hypertension (PAH). In this study, we employed the first severe PAH mouse model, EGLN1Tie2Cre (Tie2Cre-mediated disruption of EGLN1) mice, to identify the novel autocrine signaling mediating the pulmonary vascular endothelial cells (PVECs) hyperproliferation and the pathogenesis of PAH. PVECs isolated from EGLN1Tie2Cre lung expressed upregulation of many growth factors or angiocrine factors such as CXCL12, and exhib-ited hyperproliferative phenotype in coincident with upregulation of proliferation specific tran-scriptional factor FoxM1. Treatment of CXCL12 on PVECs increased FoxM1 expression, which was blocked by CXCL12 receptor CXCR4 antagonist AMD3100 in culture human PVECs. Endo-thelial specific deletion of Cxcl12 (EGLN1/Cxcl12Tie2 Cre) or AMD3100 treatment in EGLN1Tie2Cre mice downregulated FoxM1 expression in vivo. We then generated and characterized a novel mouse model with endothelial specific FoxM1 deletion in EGLN1Tie2Cre mice (EGLN1/Foxm1Tie2Cre), and found that endothelial FoxM1 deletion reduced pulmonary vascular remodeling and right ventricular systolic pressure. Together, our study identified a novel mechanism of endothelial autocrine sig-naling in regulating PVECs hyperproliferation and pulmonary vascular remodeling in PAH.
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Endothelial and Smooth Muscle Cell Interaction via FoxM1 Signaling Mediates Vascular Remodeling and Pulmonary Hypertension
American journal of respiratory and critical care medicine, 2018Co-Authors: Zhiyu Dai, Maggie M. Zhu, Xianming Zhang, Yi Peng, Hua Jin, Narsa Machireddy, Zhijian Qian, You-yang ZhaoAbstract:Rationale: Angioproliferative vasculopathy is a hallmark of pulmonary arterial hypertension (PAH). However, little is known about how endothelial cell (EC) and smooth muscle cell (SMC) crosstalk regulates the angioproliferative vascular remodeling.Objectives: To investigate the role of EC and SMC interaction and underlying signaling pathways in pulmonary hypertension (PH) development.Methods: SMC-specific Foxm1 (forkhead box M1) or Cxcr4 knockout mice, EC-specific Foxm1 or EGLN1 knockout mice, and EC-specific EGLN1/Cxcl12 double knockout mice were used to assess the role of FoxM1 on SMC proliferation and PH. Lung tissues and cells from patients with PAH were used to validate clinical relevance. FoxM1 inhibitor thiostrepton was used in Sugen 5416/hypoxia- and monocrotaline-challenged rats.Measurements and Main Results: FoxM1 expression was markedly upregulated in lungs and pulmonary arterial SMCs of patients with idiopathic PAH and four discrete PH rodent models. Mice with SMC- (but not EC-) specific delet...
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Abstract 12629: Endothelial Prolyl-4 hydroxylase 2 Deletion Induces Cardiac Hypertrophy and Heart Failure via Hypoxia Inducible Factor-2α Activation
Circulation, 2016Co-Authors: Zhiyu Dai, Maggie M. Zhu, Chen Gao, Xianming Zhang, You-yang ZhaoAbstract:Background: Cardiac hypertrophy is a common adaptive response to injury and stress, and can eventually lead to heart failure. The role of endothelial Prolyl-4 hydroxylase 2 (PHD2)/hypoxia inducible factors (HIFs) signaling in the pathogenesis of heart failure is unclear. We hypothesize that endothelial PHD2/HIF signaling dysfunction contributes to cardiac hypertrophy and heart failure. Methods: Mice with Tie2-Cre-mediated deletion of EGLN1 (encoding PHD2) ( EGLN1 Tie2-Cre ), as well as double knockout mice with both EGLN1 and Hif1a or EGLN1 and Hif2a were generated. EGLN1 f/f bone marrow cells were transplanted to lethally irradiated EGLN1 Tie2-Cre mice to determine the contribution of bone marrow cells in cardiac hypertrophy. Mice carrying EGLN1 f/f were bred into Endo SCL- Cre- ER(T) mice containing tamoxifen-inducible Cre to generate mice with EGLN1 deletion only in endothelial cells in adult mice ( EGLN1 SCL-Cre ) after tamoxifen injection. Echocardiography were measured to study cardiac size and function. Histological examination was also performed. Results: EGLN1 Tie2-Cre mice exhibited left ventricular hypertrophy evident by increased thickness of anterior and posterior wall and left ventricular mass, as well as cardiac fibrosis. EGLN1 deletion in bone marrow cells did not contribute to cardiac hypertrophy. Tamoxifen induced endothelial EGLN1 deletion in adult EGLN1 SCL-Cre mice also induced left ventricular hypertrophy and heart failure. Genetic ablation of Hif2a but not Hif1a in EGLN1 Tie2 mice normalized cardiac size and function. Additionally, we observed a marked decrease of PHD2 expression in heart tissues from patients with dilated cardiomyopathy. Conclusion: This studies define for the first time an unexpected role of endothelial PHD2 deficiency in inducing cardiac hypertrophy and heart failure in a HIF-2α dependent manner. Thus, targeting PHD2/HIF-2α signaling represents a novel therapeutic approach for the treatment of heart failure.
Frank S Lee - One of the best experts on this subject based on the ideXlab platform.
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Reply to Liu et al.: The Andean EGLN1 adaptive allele could be a loss of function variant that increases HIF1-α in skeletal muscle.
Proceedings of the National Academy of Sciences of the United States of America, 2020Co-Authors: Tom D Brutsaert, Gianpietro Elias Revollendo, Jenna L Isherwood, Frank S Lee, Sudipta Ghosh, Melissa Kiyamu, Maria Rivera-ch, Fabiola León-velarde, Abigail W BighamAbstract:We commend the work of Liu et al. (1), who show that EGLN1 is mainly expressed in skeletal muscle tissue compared to numerous other tissues examined, and that the rs1769793 T allele reduces EGLN1 expression in skeletal muscle. These findings lend plausibility to the hypothesis that the EGLN1 T-allele, which is at high frequency in Peruvian Quechua and also associated with a higher VO2max in hypoxia (2), operates through effects on skeletal muscle oxygen use and metabolism. This … [↵][1]1To whom correspondence may be addressed. Email: tdbrutsa{at}syr.edu. [1]: #xref-corresp-1-1
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an erythrocytosis associated mutation in the zinc finger of phd2 provides insights into its binding of p23
Hypoxia, 2019Co-Authors: Daisheng Song, Jennifer L Oliveira, Lea M Coon, Wei Guan, Aref Alkali, Frank S LeeAbstract:Background Loss of function mutations in the EGLN1 gene are a cause of erythrocytosis. EGLN1 encodes for prolyl hydroxylase domain protein 2 (PHD2). PHD2 hydroxylates and downregulates hypoxia-inducible factor-2α (HIF-2α), a transcription factor that regulates erythropoiesis. While the large majority of erythrocytosis-associated EGLN1 mutations occur within its catalytic domain, rare mutations reside in its zinc finger. This zinc finger binds a Pro-Xaa-Leu-Glu motif in p23, an HSP90 cochaperone that facilitates hydroxylation of HIF-α, an HSP90 client. Essentially nothing is known about the specific interactions between the PHD2 zinc finger and p23. Results Here, we characterize an erythrocytosis-associated mutation in the zinc finger, K55N, that abolishes interaction with p23. We provide evidence that the affected residue, Lys-55, interacts with Asp-152 of p23. We also present results that indicate that PHD2 Arg-32 interacts with p23 Glu-160. Conclusion These studies not only reinforce the importance of the PHD2 zinc finger in the control of erythropoiesis, but also lead to a model in which a peptide motif in p23 binds in a specific orientation to a predicted groove in the zinc finger of PHD2.
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association of EGLN1 gene with high aerobic capacity of peruvian quechua at high altitude
Proceedings of the National Academy of Sciences of the United States of America, 2019Co-Authors: Tom D Brutsaert, Melisa Kiyamu, Gianpietro Elias Revollendo, Jenna L Isherwood, Frank S Lee, Maria Riverach, Fabiola Leonvelarde, Sudipta Ghosh, Abigail W BighamAbstract:Highland native Andeans have resided at altitude for millennia. They display high aerobic capacity (VO2max) at altitude, which may be a reflection of genetic adaptation to hypoxia. Previous genomewide (GW) scans for natural selection have nominated Egl-9 homolog 1 gene (EGLN1) as a candidate gene. The encoded protein, EGLN1/PHD2, is an O2 sensor that controls levels of the Hypoxia Inducible Factor-α (HIF-α), which regulates the cellular response to hypoxia. From GW association and analysis of covariance performed on a total sample of 429 Peruvian Quechua and 94 US lowland referents, we identified 5 EGLN1 SNPs associated with higher VO2max (L⋅min−1 and mL⋅min−1⋅kg−1) in hypoxia (rs1769793, rs2064766, rs2437150, rs2491403, rs479200). For 4 of these SNPs, Quechua had the highest frequency of the advantageous (high VO2max) allele compared with 25 diverse lowland comparison populations from the 1000 Genomes Project. Genotype effects were substantial, with high versus low VO2max genotype categories differing by ∼11% (e.g., for rs1769793 SNP genotype TT = 34.2 mL⋅min−1⋅kg−1 vs. CC = 30.5 mL⋅min−1⋅kg−1). To guard against spurious association, we controlled for population stratification. Findings were replicated for EGLN1 SNP rs1769793 in an independent Andean sample collected in 2002. These findings contextualize previous reports of natural selection at EGLN1 in Andeans, and support the hypothesis that natural selection has increased the frequency of an EGLN1 causal variant that enhances O2 delivery or use during exercise at altitude in Peruvian Quechua.
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The Zinc Finger of Prolyl Hydroxylase Domain Protein 2 Is Essential for Efficient Hydroxylation of Hypoxia-Inducible Factor α.
Molecular and cellular biology, 2016Co-Authors: Patrick R. Arsenault, Daisheng Song, Yu Jin Chung, Tejvir S. Khurana, Frank S LeeAbstract:Prolyl hydroxylase domain protein 2 (PHD2) (also known as EGLN1) is a key oxygen sensor in mammals that posttranslationally modifies hypoxia-inducible factor α (HIF-α) and targets it for degradation. In addition to its catalytic domain, PHD2 contains an evolutionarily conserved zinc finger domain, which we have previously proposed recruits PHD2 to the HSP90 pathway to promote HIF-α hydroxylation. Here, we provide evidence that this recruitment is critical both in vitro and in vivo We show that in vitro, the zinc finger can function as an autonomous recruitment domain to facilitate interaction with HIF-α. In vivo, ablation of zinc finger function by a C36S/C42S EGLN1 knock-in mutation results in upregulation of the erythropoietin gene, erythrocytosis, and augmented hypoxic ventilatory response, all hallmarks of EGLN1 loss of function and HIF stabilization. Hence, the zinc finger ordinarily performs a critical positive regulatory function. Intriguingly, the function of this zinc finger is impaired in high-altitude-adapted Tibetans, suggesting that their adaptation to high altitude may, in part, be due to a loss-of-function EGLN1 allele. Thus, these findings have important implications for understanding both the molecular mechanism of the hypoxic response and human adaptation to high altitude.
Desheng Xiao - One of the best experts on this subject based on the ideXlab platform.
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EGLN1/c-Myc Induced Lymphoid-Specific Helicase Inhibits Ferroptosis through Lipid Metabolic Gene Expression Changes
Theranostics, 2017Co-Authors: Yiqun Jiang, Chao Mao, Rui Yang, Bin Yan, Ying Shi, Xiaoli Liu, Weiwei Lai, Yating Liu, Xiang Wang, Desheng XiaoAbstract:Ferroptosis is a newly discovered form of non-apoptotic cell death in multiple human diseases. However, the epigenetic mechanisms underlying ferroptosis remain poorly defined. First, we demonstrated that lymphoid-specific helicase (LSH), which is a DNA methylation modifier, interacted with WDR76 to inhibit ferroptosis by activating lipid metabolism-associated genes, including GLUT1, and ferroptosis related genes SCD1 and FADS2, in turn, involved in the Warburg effect. WDR76 targeted these genes expression in dependent manner of LSH and chromatin modification in DNA methylation and histone modification. These effects were dependent on iron and lipid reactive oxygen species. We further demonstrated that EGLN1 and c-Myc directly activated the expression of LSH by inhibiting HIF-1α. Finally, we demonstrated that LSH functioned as an oncogene in lung cancer in vitro and in vivo. Therefore, our study elucidates the molecular basis of the c-Myc/EGLN1-mediated induction of LSH expression that inhibits ferroptosis, which can be exploited for the development of therapeutic strategies targeting ferroptosis for the treatment of cancer.
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EGLN1 c myc induced lymphoid specific helicase inhibits ferroptosis through lipid metabolic gene expression changes
Theranostics, 2017Co-Authors: Yiqun Jiang, Chao Mao, Rui Yang, Bin Yan, Ying Shi, Xiaoli Liu, Weiwei Lai, Yating Liu, Xiang Wang, Desheng XiaoAbstract:Ferroptosis is a newly discovered form of non-apoptotic cell death in multiple human diseases. However, the epigenetic mechanisms underlying ferroptosis remain poorly defined. First, we demonstrated that lymphoid-specific helicase (LSH), which is a DNA methylation modifier, interacted with WDR76 to inhibit ferroptosis by activating lipid metabolism-associated genes, including GLUT1, and ferroptosis related genes SCD1 and FADS2, in turn, involved in the Warburg effect. WDR76 targeted these genes expression in dependent manner of LSH and chromatin modification in DNA methylation and histone modification. These effects were dependent on iron and lipid reactive oxygen species. We further demonstrated that EGLN1 and c-Myc directly activated the expression of LSH by inhibiting HIF-1α. Finally, we demonstrated that LSH functioned as an oncogene in lung cancer in vitro and in vivo. Therefore, our study elucidates the molecular basis of the c-Myc/EGLN1-mediated induction of LSH expression that inhibits ferroptosis, which can be exploited for the development of therapeutic strategies targeting ferroptosis for the treatment of cancer.