Advanced age is an independent risk factor for ageing-related complex diseases, such as coronary artery disease, stroke, and hypertension, which are common but life threatening and related to the ageing-associated vas...Advanced age is an independent risk factor for ageing-related complex diseases, such as coronary artery disease, stroke, and hypertension, which are common but life threatening and related to the ageing-associated vascular dysfunction. On the other hand, patients with progeria syndromes suffer from serious atherosclerosis, suggesting that the impaired vascular functions may be critical to organismal ageing, or vice versa. However, it remains largely unknown how vascular cells, particularly endothelial cell, become senescent and how the senescence impairs the vascular functions and contributes to the age-related vascular diseases over time. Here, we review the recent progress on the characteristics of vascular ageing and endothelial cell senescence in vitro and in vivo, evaluate how genetic and envi- ronmental factors as well as autophagy and stem cell influence endothelial cell senescence and how the senescence contributes to the age- related vascular phenotypes, such as atherosclerosis and increased vascular stiffness, and explore the possibility whether we can delay the age-related vascular diseases through the control of vascular ageing.展开更多
Type 2 diabetes mellitus(T2 DM)is a common metabolic disease influenced by both genetic and environmental factors.In this study,we performed an in-house genotyping and meta-analysis study using three independent GWAS ...Type 2 diabetes mellitus(T2 DM)is a common metabolic disease influenced by both genetic and environmental factors.In this study,we performed an in-house genotyping and meta-analysis study using three independent GWAS datasets of T2 DM and found that rs3743121,located 1 kb downstream of AQR,was a novel susceptibility SNP associated with T2 DM.The risk allele C of rs3743121 was correlated with the increased expression of AQR in white blood cells,similar to that observed in T2 DM models.The knockdown of AQR in HepG2 facilitated the glucose uptake,decreased the expression level of PCK2,increased the phosphorylation of GSK-3β,and restored the insulin sensitivity.Furthermore,the suppression of AQR inhibited the mTOR pathway and the protein ubiquitination process.Our study suggests that AQR is a novel type 2 diabetes-associated gene that regulates signaling pathways critical for glucose metabolism.展开更多
The aim of this study was to examine how somatic mutations of the GATA4 gene contributed to the genesis of ventricular septal defect （VSD）. The coding and intron-exon boundary regions of GATA4 were sequenced of DNA ...The aim of this study was to examine how somatic mutations of the GATA4 gene contributed to the genesis of ventricular septal defect （VSD）. The coding and intron-exon boundary regions of GATA4 were sequenced of DNA samples from peripheral blood cells and cardiac tissues of twenty surgically treated probands with VSD. Seven novel heterozygous variants were detected in cardiac tissues from VSD patients, but they were not detected in the peripheral blood cells of VSD patients or in 500 healthy control samples. We replicated 14 single nucleotide polymorphisms （SNPs） reported in NCBI. Bioinformatics analysis was performed to analyze the possible mechanism by which mutations were linked to VSD. Among those variants, c. 1004C〉A （p.S335X） occurred in the highly conserved domain of GATA4 and generated a termination codon, which led to the production of truncated GATA4. The seven novel heterozygous GATA4 mutations were only identified in cardiac tissues with VSD, suggesting that they are of somatic origin. A higher mutation rate in cardiac tissues than in peripheral blood cells implies that the genetic contribution to VSD may have been underestimated.展开更多
Angiogenic factor with G-patch and FHA domains 1(AGGF1)exhibits a dynamic distribution from the nucleus to the cytoplasm in endothelial cells during angiogenesis,but the biological significance and underlying mechanis...Angiogenic factor with G-patch and FHA domains 1(AGGF1)exhibits a dynamic distribution from the nucleus to the cytoplasm in endothelial cells during angiogenesis,but the biological significance and underlying mechanism of this nucleocytoplasmic transport remains unknown.Here,we demonstrate that the dynamic distribution is essential for AGGF1 to execute its angiogenic function.To search the structural bases for this nucleocytoplasmic transport,we characterized three potential nuclear localization regions,one potential nuclear export region,forkhead-associated(FHA),and G-patch domains to determine their effects on nucleocytoplasmic transport and angiogenesis,and we show that AGGF1 remains intact during the dynamic subcellular distribution and the region from 260 to 288 amino acids acts as a signal for its nuclear localization.The distribution of AGGF1 in cytoplasm needs both FHA domain and 14-3-3α/β.Binding of AGGF1 via FHA domain to 14-3-3α/βis required to complete the transport.Thus,we for the first time established structural bases for the nucleocytoplasmic transport of AGGF1 and revealed that the FHA domain of AGGF1 is essential for its nucleocytoplasmic transport and angiogenesis.展开更多
基金supported by the National Basic Research Program of the Chinese Ministry of Science and Technology to XLT(No.2013CB530700)
文摘Advanced age is an independent risk factor for ageing-related complex diseases, such as coronary artery disease, stroke, and hypertension, which are common but life threatening and related to the ageing-associated vascular dysfunction. On the other hand, patients with progeria syndromes suffer from serious atherosclerosis, suggesting that the impaired vascular functions may be critical to organismal ageing, or vice versa. However, it remains largely unknown how vascular cells, particularly endothelial cell, become senescent and how the senescence impairs the vascular functions and contributes to the age-related vascular diseases over time. Here, we review the recent progress on the characteristics of vascular ageing and endothelial cell senescence in vitro and in vivo, evaluate how genetic and envi- ronmental factors as well as autophagy and stem cell influence endothelial cell senescence and how the senescence contributes to the age- related vascular phenotypes, such as atherosclerosis and increased vascular stiffness, and explore the possibility whether we can delay the age-related vascular diseases through the control of vascular ageing.
基金supported by the National Basic Research Program of the Chinese Ministry of Science and Technology(2013CB530700)Key Programs from the National Natural Science Foundation of China(Nos.81630034 and 81130003)
文摘Type 2 diabetes mellitus(T2 DM)is a common metabolic disease influenced by both genetic and environmental factors.In this study,we performed an in-house genotyping and meta-analysis study using three independent GWAS datasets of T2 DM and found that rs3743121,located 1 kb downstream of AQR,was a novel susceptibility SNP associated with T2 DM.The risk allele C of rs3743121 was correlated with the increased expression of AQR in white blood cells,similar to that observed in T2 DM models.The knockdown of AQR in HepG2 facilitated the glucose uptake,decreased the expression level of PCK2,increased the phosphorylation of GSK-3β,and restored the insulin sensitivity.Furthermore,the suppression of AQR inhibited the mTOR pathway and the protein ubiquitination process.Our study suggests that AQR is a novel type 2 diabetes-associated gene that regulates signaling pathways critical for glucose metabolism.
基金supported by National Natural Science Fund of China (No.30871079)National Science Foundation of Jiangsu province (No. BK2007232)
文摘The aim of this study was to examine how somatic mutations of the GATA4 gene contributed to the genesis of ventricular septal defect （VSD）. The coding and intron-exon boundary regions of GATA4 were sequenced of DNA samples from peripheral blood cells and cardiac tissues of twenty surgically treated probands with VSD. Seven novel heterozygous variants were detected in cardiac tissues from VSD patients, but they were not detected in the peripheral blood cells of VSD patients or in 500 healthy control samples. We replicated 14 single nucleotide polymorphisms （SNPs） reported in NCBI. Bioinformatics analysis was performed to analyze the possible mechanism by which mutations were linked to VSD. Among those variants, c. 1004C〉A （p.S335X） occurred in the highly conserved domain of GATA4 and generated a termination codon, which led to the production of truncated GATA4. The seven novel heterozygous GATA4 mutations were only identified in cardiac tissues with VSD, suggesting that they are of somatic origin. A higher mutation rate in cardiac tissues than in peripheral blood cells implies that the genetic contribution to VSD may have been underestimated.
基金This work was supported by grants from the National Natural Science Foundation of China(30730047,81070262,81130003 and 81630034).
文摘Angiogenic factor with G-patch and FHA domains 1(AGGF1)exhibits a dynamic distribution from the nucleus to the cytoplasm in endothelial cells during angiogenesis,but the biological significance and underlying mechanism of this nucleocytoplasmic transport remains unknown.Here,we demonstrate that the dynamic distribution is essential for AGGF1 to execute its angiogenic function.To search the structural bases for this nucleocytoplasmic transport,we characterized three potential nuclear localization regions,one potential nuclear export region,forkhead-associated(FHA),and G-patch domains to determine their effects on nucleocytoplasmic transport and angiogenesis,and we show that AGGF1 remains intact during the dynamic subcellular distribution and the region from 260 to 288 amino acids acts as a signal for its nuclear localization.The distribution of AGGF1 in cytoplasm needs both FHA domain and 14-3-3α/β.Binding of AGGF1 via FHA domain to 14-3-3α/βis required to complete the transport.Thus,we for the first time established structural bases for the nucleocytoplasmic transport of AGGF1 and revealed that the FHA domain of AGGF1 is essential for its nucleocytoplasmic transport and angiogenesis.
