-
[show abstract]
[hide abstract]
ABSTRACT: Intercellular adhesion molecule-1 (ICAM-1) plays an important role in the recruitment of leukocytes to the endothelium, which causes inflammation and initiation of atherosclerosis. We have previously shown that endothelium-specific over-expression of class III deacetylase SIRT1 decreases atherosclerosis. We therefore addressed the hypothesis that SIRT1 suppresses ICAM-1 expression in the endothelial cells. Here, we found that expression of SIRT1 and ICAM-1 was significantly induced by PMA and ionomycin (PMA/Io) in human umbilical vein endothelial cells (HUVECs). Adenovirus-mediated over-expression of SIRT1 significantly inhibited PMA/Io-induced ICAM-1 expression in HUVECs. Knockdown of SIRT1 by RNA interference (RNAi) resulted in increased expression of ICAM-1 in HUVECs. Luciferase report assay showed that over-expression of SIRT1 suppressed ICAM-1 promoter activity both in basic and in PMA/Io-induced conditions. We further found that SIRT1 was involved in transcription complex binding on the ICAM-1 promoter by chromatin immunoprecipitation (ChIP) assays. Furthermore, SIRT1 RNAi increased NF-κB p65 binding ability to the ICAM-1 promoter by ChIP assays. Overall, these data suggests that SIRT1 inhibits ICAM-1 expression in endothelial cells, which may contribute to its anti-atherosclerosis effect.
Science China. Life sciences 12/2012; · 2.02 Impact Factor
-
Casey M. Rebholz,
Dongfeng Gu,
Jing Chen,
Jian-Feng Huang,
Jie Cao,
Ji-Chun Chen,
Jianxin Li,
Fanghong Lu,
Jianjun Mu,
Jixiang Ma,
Dongsheng Hu,
Xu Ji,
Lydia A. Bazzano, Depei Liu,
Jiang He,
for the GenSalt Collaborative Research Group
[show abstract]
[hide abstract]
ABSTRACT: Salt sensitivity of blood pressure (BP) is influenced by genetic and environmental factors. A dietary feeding
study was conducted from October 2003 to July 2005 that included a 7-day low-sodium intervention (51.3 mmol sodium/day) followed by a 7-day high-sodium intervention (307.8 mmol sodium/day) among 1,906 individuals who were 16 years of age or older and living in rural northern China. Salt sensitivity of BP was defined as mean BP change from the low-sodium intervention to the high-sodium intervention. Usual physical activity during the past 12 months was assessed at baseline using a standard questionnaire. The multivariable-adjusted means of systolic BP responses to high-sodium intervention were 5.21 mm Hg (95% confidence interval (CI): 4.55, 5.88), 4.97 mm Hg (95% CI: 4.35, 5.59), 5.02 mm Hg (95% CI: 4.38, 5.67), and 3.96 mm Hg (95% CI: 3.29, 4.63) among participants from the lowest to the highest quartiles of physical activity, respectively (P = 0.003 for linear trend). The multivariable-adjusted odds ratio of high salt sensitivity of systolic BP was 0.66 (95% CI: 0.49, 0.88) for persons in the highest quartile of physical activity compared with those in the lowest quartile. Physical activity is significantly, independently, and inversely related to salt sensitivity of BP and may be particularly effective in lowering BP among salt-sensitive individuals.
American Journal of Epidemiology 10/2012; 176(7):S106–S113. · 5.22 Impact Factor
-
Xiangfeng Lu,
Laiyuan Wang,
Shufeng Chen,
Lin He,
Xueli Yang,
Yongyong Shi,
Jing Cheng,
Liang Zhang,
C Charles Gu,
Jianfeng Huang, [......],
Sekar Kathiresan,
Muredach P Reilly,
Jeanette Erdmann,
Xiaozhong Peng,
Xigui Wu, Depei Liu,
Yuejin Yang,
Runsheng Chen,
Boqin Qiang,
Dongfeng Gu
[show abstract]
[hide abstract]
ABSTRACT: We performed a meta-analysis of 2 genome-wide association studies of coronary artery disease comprising 1,515 cases and 5,019 controls followed by replication studies in 15,460 cases and 11,472 controls, all of Chinese Han ancestry. We identify four new loci for coronary artery disease that reached the threshold of genome-wide significance (P < 5 × 10(-8)). These loci mapped in or near TTC32-WDR35, GUCY1A3, C6orf10-BTNL2 and ATP2B1. We also replicated four loci previously identified in European populations (in or near PHACTR1, TCF21, CDKN2A-CDKN2B and C12orf51). These findings provide new insights into pathways contributing to the susceptibility for coronary artery disease in the Chinese Han population.
Nature Genetics 07/2012; 44(8):890-4. · 35.53 Impact Factor
-
Houzao Chen,
Yanzhen Wan,
Shuang Zhou,
Yunbiao Lu,
Zhuqin Zhang,
Ran Zhang,
Feng Chen,
Delong Hao,
Xiang Zhao,
Zhichen Guo, Depei Liu,
Chihchuan Liang
[show abstract]
[hide abstract]
ABSTRACT: The rapidly increasing prevalence of diabetes mellitus worldwide is one of the most serious and challenging health problems in the 21st century. Mammalian sirtuin 1 (SIRT1) has been shown to decrease high-glucose-induced endothelial cell senescence in vitro and prevent hyperglycemia-induced vascular dysfunction. However, a role for SIRT1 in prevention of hyperglycemia-induced vascular cell senescence in vivo remains unclear. We used endothelium-specific SIRT1 transgenic (SIRT1-Tg) mice and wild-type (WT) mice to construct a 40-week streptozotocin (STZ)-induced diabetic mouse model. In this mode, 42.9% of wild-type (WT) mice and 38.5% of SIRT1-Tg mice were successfully established as diabetic. Forty weeks of hyperglycemia induced significant vascular cell senescence in aortas of mice, as indicated by upregulation of expression of senescence-associated markers including p53, p21 and plasminogen activator inhibitor-1 (PAI-1). However, SIRT1-Tg diabetic mice displayed dramatically decreased expression of p53, p21 and PAI-1 compared with diabetic WT mice. Moreover, manganese superoxide dismutase expression (MnSOD) was significantly downregulated in the aortas of diabetic WT mice, but was preserved in diabetic SIRT1-Tg mice. Furthermore, expression of the oxidative stress adaptor p66Shc was significantly decreased in aortas of SIRT1-Tg diabetic mice compared with WT diabetic mice. Overall, these findings suggest that SIRT1-mediated inhibition of hyperglycemia-induced vascular cell senescence is mediated at least partly through the reduction of oxidative stress.
Science China. Life sciences 06/2012; 55(6):467-73. · 2.02 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Acyl-coenzyme A:cholesterol acyltransferase 2 (ACAT2) is important for cholesterol ester synthesis and secretion. A previous study revealed that ACAT2 gene promoter activity was upregulated by hepatocyte nuclear factor 4α (HNF4α) through two sites around -247 and -311 of ACAT2 gene promoter. Here, we identified two novel cis-elements, site I (-1006 to -898) and site II (-38 to -29), which are important for HNF4α effect. In HepG2 cells, mutation of site I decreased ACAT2 gene promoter activity to one-fifth of that of the wild type, while mutation of site II reduced promoter activity to less than one-tenth of that of the wild type. In 293T cells, mutation of these two cis-elements profoundly impaired the HNF4α induction effect. When either of these two elements was inserted into pGL3-promoter, HNF4α induced promoter activity through the inserted element, while mutation of the element impaired HNF4α induction effect. In electrophoretic mobility shift assay and chromatin immunoprecipitation experiment, HNF4α bound to these two elements. Thus, the two cis-elements are important for HNF4α effect on ACAT2 gene transcription. We also showed that HNF4α positively regulates ACAT2 gene expression at mRNA level. Overexpression of HNF4α increased ACAT2 expression, whereas knockdown of HNF4α decreased ACAT2 expression. Peroxisome proliferator-activated receptor gamma coactivator 1α (PCG1α), a coactivator of HNF4α, increased ACAT2 expression, while small heterodimer partner (SHP), a corepressor of HNF4α, decreased ACAT2 expression. These results provide more insights into transcriptional regulation of ACAT2 expression.
Acta Biochimica et Biophysica Sinica 12/2011; 44(2):162-71. · 1.38 Impact Factor
-
Science China. Life sciences 12/2011; 54(12):1085-8. · 2.02 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Angiotensin II (Ang II) stimulates vascular smooth muscle cell (VSMC) hypertrophy as a critical event in the development of vascular diseases such as atherosclerosis. Sirtuin (SIRT) 1, a nicotinamide adenine dinucleotide dependent deacetylase, has been demonstrated to exert protective effects in atherosclerosis by promoting endothelium-dependent vascular relaxation and reducing macrophage foam cell formation, but its role in VSMC hypertrophy remains unknown. In this study, we tried to investigate the effect of SIRT1 on Ang II-induced VSMC hypertrophy. Results showed that adenoviral-mediated over-expression of SIRT1 significantly inhibited Ang II-induced VSMC hypertrophy, while knockdown of SIRT1 by RNAi resulted in an increased [(3)H]-leucine incorporation of VSMC. Accordingly, nicotinamide adenine dinucleotide phosphate oxidase 1 (Nox1) expression induced by Ang II was inhibited by SIRT1 in VSMCs. SIRT1 activator resveratrol decreased, whereas endogenous SIRT1 inhibitor nicotinamide increased Nox1 expression in A7r5 VSMCs. Furthermore, transcription factor GATA-6 was involved in the down-regulation of Nox1 expression by SIRT1. These results provide new insight into SIRT1's anti-atherogenic properties by suppressing Ang II-induced VSMC hypertrophy.
Acta Biochimica et Biophysica Sinica 02/2011; 43(2):103-9. · 1.38 Impact Factor
-
Tanika N Kelly,
James E Hixson,
Dabeeru C Rao,
Hao Mei,
Treva K Rice,
Cashell E Jaquish,
Lawrence C Shimmin,
Karen Schwander,
Chung-Shuian Chen, Depei Liu,
Jichun Chen,
Concetta Bormans,
Pramila Shukla,
Naveed Farhana,
Colin Stuart,
Paul K Whelton,
Jiang He,
Dongfeng Gu
[show abstract]
[hide abstract]
ABSTRACT: Genetic determinants of blood pressure (BP) response to potassium, or potassium sensitivity, are largely unknown. We conducted a genome-wide linkage scan and positional candidate gene analysis to identify genetic determinants of potassium sensitivity.
A total of 1906 Han Chinese participants took part in a 7-day high-sodium diet followed by a 7-day high-sodium plus potassium dietary intervention. BP measurements were obtained at baseline and after each intervention using a random-zero sphygmomanometer. Significant linkage signals (logarithm of odds [LOD] score, >3) for BP responses to potassium were detected at chromosomal regions 3q24-q26.1, 3q28, and 11q22.3-q24.3. Maximum multipoint LOD scores of 3.09 at 3q25.2 and 3.41 at 11q23.3 were observed for absolute diastolic BP (DBP) and mean arterial pressure (MAP) responses, respectively. Linkage peaks of 3.56 at 3q25.1 and 3.01 at 11q23.3 for percent DBP response and 3.22 at 3q25.2, 3.01 at 3q28, and 4.48 at 11q23.3 for percent MAP response also were identified. Angiotensin II receptor, type 1 (AGTR1), single-nucleotide polymorphism rs16860760 in the 3q24-q26.1 region was significantly associated with absolute and percent systolic BP responses to potassium (P=0.0008 and P=0.0006, respectively). Absolute (95% CI) systolic BP responses for genotypes C/C, C/T, and T/T were -3.71 (-4.02 to -3.40), -2.62 (-3.38 to -1.85), and 1.03 (-3.73 to 5.79) mm Hg, respectively, and percent responses (95% CI) were -3.07 (-3.33 to -2.80), -2.07 (-2.74 to -1.41), and 0.90 (-3.20 to 4.99), respectively. Similar trends were observed for DBP and MAP responses.
Genetic regions on chromosomes 3 and 11 may harbor important susceptibility loci for potassium sensitivity. Furthermore, the AGTR1 gene was a significant predictor of BP responses to potassium intake.
Circulation Cardiovascular Genetics 12/2010; 3(6):539-47. · 6.11 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The proinflammatory cytokine TNF-alpha plays an important role in stimulating inflammatory responses of vascular smooth muscle cells (VSMCs). The anti-inflammatory function of Sirtuin 1 (SIRT1), a NAD-dependent class III histone/protein deacetylase, has been well documented, but how SIRT1 is regulated under inflammatory conditions is largely unknown. In the present research, we showed that levels of SIRT1 mRNA and protein expression increased in TNF-alpha-treated VSMCs. Overexpression of the p65/RelA subunit of NF-kappaB, a TNF-alpha-activated inflammatory transcription factor, in A7r5 cells, up-regulated SIRT1 mRNA and protein expression as well as SIRT1 promoter activity, while knockdown of endogenous p65/RelA expression by RNAi not only led to a decrease in SIRT1's basal protein expression and promoter activity, but almost abolished the TNF-alpha-induced elevation of SIRT1 protein expression and SIRT1 promoter activity. Furthermore, using promoter deletion analysis and chromatin immunoprecipitation assays, we found that p65/RelA bound to the SIRT1 promoter at a consensus NF-kappaB binding site. Our study indicates that p65/RelA mediates the TNF-alpha-induced elevated expression of SIRT1 in VSMCs, shedding new light on the regulation of SIRT1 under inflammatory conditions.
Biochemical and Biophysical Research Communications 06/2010; · 2.48 Impact Factor
-
Dongfeng Gu,
Tanika N Kelly,
James E Hixson,
Jing Chen, Depei Liu,
Ji-chun Chen,
Dabeeru C Rao,
Jianjun Mu,
Jixiang Ma,
Cashell E Jaquish,
Treva K Rice,
Charles Gu,
L Lee Hamm,
Paul K Whelton,
Jiang He
[show abstract]
[hide abstract]
ABSTRACT: To examine the association between renin-angiotensin-aldosterone system (RAAS) genes and salt sensitivity of blood pressure (BP).
A 7-day low-sodium dietary intervention followed by a 7-day high-sodium dietary intervention was conducted among 1906 participants living in a rural region of north China where habitual sodium intake is high. BP measurements were obtained at baseline and following each intervention using a random-zero sphygmomanometer.
DBP and mean arterial pressure responses increased with the number of rs4524238 A alleles in the angiotensin II receptor type 1 gene. For example, mean DBP responses (95% confidence interval) among those with genotypes G/G, G/A, and A/A were -2.53 (-2.89 to -2.18), -3.49 (-4.13 to -2.86), and -5.78 (-9.51 to -2.06) mmHg, respectively, following the low-sodium intervention (P=0.0008). Carriers of the rare A allele of rs5479 in the hydroxysteroid (11-beta) dehydrogenase 2 gene had decreased DBP responses to low sodium (P=0.00004). Those with the C/A and C/C genotypes had DBP responses of -0.70 (-6.62 to 5.22) and -2.71 (-4.88 to -0.54) mmHg, respectively. X chromosome renin-binding protein gene markers rs1557501 and rs2269372 were associated with SBP response to low sodium in men (P=0.00004 and 0.0001, respectively). SBP responses (95% confidence interval) were -6.13 (-6.68 to -5.58) versus -4.07 (-4.88 to -3.26) and -6.04 (-6.57 to -5.52) versus -3.94 (-4.90 to -2.99) mmHg among men with major versus those with minor alleles of rs1557501 and rs2269372, respectively. Haplotype analyses of these genes supported our single-marker findings.
We identified renin-angiotensin-aldosterone system variants that were predictive of salt sensitivity in a Han population with habitually high-sodium intake.
Journal of hypertension 06/2010; 28(6):1210-20. · 4.02 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Glioma-specific transcription of tumor-killing genes has been exploited as a promising gene therapeutic modality in glioma patients. Musashi1 (Msi1) and GFAP gene promoters are both cancer-specific promoters. Optimized HIF-binding site (optHBS) sequence was newly found as efficient as EPO HREs used as enhancer in cancer gene therapy. We constructed 4optHBS-Msi1/GFAP promoters and tested their ability to mediate BAX expression to induce apoptosis in glioma cell lines. Our results demonstrated that 4optHBS-Msi1/GFAP promoters are apparently strong and glioma-selective promoters with potential application in targeted glioma gene therapy, and 4optHBS-Msi1/GFAPBAXa are valuable tools for glioma gene therapy.
Acta Biochimica et Biophysica Sinica 04/2010; 42(4):274-80. · 1.38 Impact Factor
-
Tanika N Kelly,
Treva K Rice,
Dongfeng Gu,
James E Hixson,
Jing Chen, Depei Liu,
Cashell E Jaquish,
Lydia A Bazzano,
Dongsheng Hu,
Jixiang Ma,
C Charles Gu,
Jianfeng Huang,
L Lee Hamm,
Jiang He
[show abstract]
[hide abstract]
ABSTRACT: We examined the association between 12 single-nucleotide polymorphisms (SNPs) in the alpha-adducin (ADD1) and guanine nucleotide binding protein (G protein) beta-polypeptide 3 (GNB3) genes and systolic (SBP), diastolic (DBP), and mean arterial (MAP) pressure responses to salt intake.
A 7-day low-sodium (51.3 mmol sodium/day) followed by a 7-day high-sodium intervention (307.8 mmol sodium/day) was conducted among 1,906 Han participants from rural North China. Blood pressure (BP) measurements were obtained at baseline and at the end of each intervention period using a random-zero sphygmomanometer.
We identified a significant association between a rare ADD1 variant rs17833172 and SBP, DBP, and MAP responses to high sodium (P values <0.0001) and DBP response to low sodium (P value = 0.002). Participants homozygous for the variant A allele of this marker had SBP, DBP, and MAP responses (95% confidence interval) to high salt of 1.6 (-1.8, 4.9), -0.8 (-5.6, 4.0), and -0.1 (-4.0, 3.9) mm Hg, respectively, vs. corresponding responses of 4.6 (2.5, 6.6), 1.7 (-0.2, 3.6), and 2.7 (0.9, 4.4) mm Hg, respectively, for those who were heterozygous or homozygous for the G allele. In addition, participants with at least one copy of the A allele of SNP rs1129649 of the GNB3 gene had significantly decreased MAP response to low salt compared to homozygotes for the C allele (P value = 0.004) with responses of -3.4 (-3.8, -3.0) vs. -4.2 (-4.6, -3.8) mm Hg, respectively.
These data support a role for the ADD1 and GNB3 genes in BP salt sensitivity. Future studies aimed at replicating these novel findings are warranted.
American Journal of Hypertension 08/2009; 22(9):985-92. · 3.18 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Wnt signaling plays an important role in regulating cortical and hippocampal development, but many of the other molecular mechanisms underlying dorsal telencephalic development are largely unknown. We are taking advantage of the highly regionalized expression patterns of signaling components of the Wnt pathway to generate new mouse lines that will be useful for studying forebrain development. Here, we describe a transgenic mouse line where Cre is driven by the promoter of the Wnt receptor, Frizzled10. In these mice, Cre activity is mainly detected in the dorsal telencephalon during development and is confined to the pyramidal cell fields in the adult hippocampus. The Cre recombinase has very high efficiency when assayed by crossing the transgenic line with the ROSA26 reporter line. Thus, this Cre line will be useful for the study of dorsal telencephalic development and conditional inactivation of target genes in the cortex and hippocampus.
genesis 10/2008; 46(10):523-9. · 2.53 Impact Factor
-
Jing Chen,
Dongfeng Gu,
Cashell E Jaquish,
Chung-Shiuan Chen,
D C Rao, Depei Liu,
James E Hixson,
L Lee Hamm,
C Charles Gu,
Paul K Whelton,
Jiang He
[show abstract]
[hide abstract]
ABSTRACT: Blood pressure (BP) responses to the cold pressor test (CPT) and to dietary sodium intake might be related to the risk of hypertension. We examined the association between BP responses to the CPT and to dietary sodium and potassium interventions.
The CPT and dietary intervention were conducted among 1906 study participants in rural China. The dietary intervention included three 7-day periods of low sodium intake (3 g/d of salt [sodium chloride] [51.3 mmol/d of sodium]), high sodium intake (18 g/d of salt [307.8 mmol/d of sodium]), and high sodium intake plus potassium chloride supplementation (60 mmol/d). A total of 9 BP measurements were obtained during the 3-day baseline observation and the last 3 days of each intervention using a random-zero sphygmomanometer.
Blood pressure response to the CPT was significantly associated with BP changes during the sodium and potassium interventions (all P < .001). Compared with the lowest quartile of BP response to the CPT (quartile 1), systolic BP changes (95% confidence intervals) for the quartiles 2, 3, and 4 were -2.02 (-2.87 to -1.16) mm Hg, -3.17 (-4.05 to -2.28) mm Hg, and -5.98 (-6.89 to -5.08) mm Hg, respectively, during the low-sodium intervention. Corresponding systolic BP changes during the high-sodium intervention were 0.40 (-0.36 to 1.16) mm Hg, 0.44 (-0.35 to 1.22) mm Hg, and 2.30 (1.50 to 3.10) mm Hg, respectively, and during the high-sodium plus potassium supplementation intervention were -0.26 (-0.99 to 0.46) mm Hg, -0.95 (-1.70 to -0.20) mm Hg, and -1.59 (-2.36 to -0.83) mm Hg, respectively.
These results indicate that BP response to the CPT was associated with salt sensitivity and potassium sensitivity. Furthermore, a low-sodium or high-potassium diet might be more effective to lower BP among individuals with high responses to the CPT.
Archives of internal medicine 09/2008; 168(16):1740-6. · 11.46 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC) is the largest medical institution in China and has a leading high-level multidisciplinary medical research and medial service. Under the CAMS and PUMC infrastructure, there are 17 biomedical institutes and 6 large hospitals, which cover most fields of the human disease-related research. CAMS and PUMC has always attached great emphasis on the control and cure of severe diseases, as well as a series of innovative drug researches, and has made significant progress in those fields. The long-term goals for CAMS and PUMC in the future development are: reaching the international advanced level in the areas of severe disease prediction, prevention, control, diagnosis, and research on drug innovation; establishing theoretical and technological system for explanation of the mechanism of severe diseases, which possesses Chinese style and represents the frontier level in the world, and at the same time, providing scientific support for the prevention and treatment of severe disease and making contribution to the establishment and development of a harmonious society in China.
Journal of Molecular Medicine 09/2007; 85(8):845-50. · 4.67 Impact Factor
-
Keiji Kuba,
Yumiko Imai,
Shuan Rao,
Hong Gao,
Feng Guo,
Bin Guan,
Yi Huan,
Peng Yang,
Yanli Zhang,
Wei Deng, [......],
Mark Chappell,
Yanxin Liu,
Dexian Zheng,
Andreas Leibbrandt,
Teiji Wada,
Arthur S Slutsky, Depei Liu,
Chuan Qin,
Chengyu Jiang,
Josef M Penninger
[show abstract]
[hide abstract]
ABSTRACT: During several months of 2003, a newly identified illness termed severe acute respiratory syndrome (SARS) spread rapidly through the world. A new coronavirus (SARS-CoV) was identified as the SARS pathogen, which triggered severe pneumonia and acute, often lethal, lung failure. Moreover, among infected individuals influenza such as the Spanish flu and the emergence of new respiratory disease viruses have caused high lethality resulting from acute lung failure. In cell lines, angiotensin-converting enzyme 2 (ACE2) has been identified as a potential SARS-CoV receptor. The high lethality of SARS-CoV infections, its enormous economic and social impact, fears of renewed outbreaks as well as the potential misuse of such viruses as biologic weapons make it paramount to understand the pathogenesis of SARS-CoV. Here we provide the first genetic proof that ACE2 is a crucial SARS-CoV receptor in vivo. SARS-CoV infections and the Spike protein of the SARS-CoV reduce ACE2 expression. Notably, injection of SARS-CoV Spike into mice worsens acute lung failure in vivo that can be attenuated by blocking the renin-angiotensin pathway. These results provide a molecular explanation why SARS-CoV infections cause severe and often lethal lung failure and suggest a rational therapy for SARS and possibly other respiratory disease viruses.
Nature Medicine 09/2005; 11(8):875-9. · 22.46 Impact Factor
-
Chuan Qin,
Jianwei Wang,
Qiang Wei,
Mingpeng She,
Wayne A Marasco,
Hong Jiang,
Xinming Tu,
Hua Zhu,
Lili Ren,
Hong Gao, [......],
Wei Tong,
Li Ruan,
Peimao Liu,
Hua Zhang,
Jianmin Zhang,
Huiyuan Zhang, Depei Liu,
Qian Liu,
Tao Hong,
Wei He
[show abstract]
[hide abstract]
ABSTRACT: A new SARS animal model was established by inoculating SARS coronavirus (SARS-CoV) into rhesus macaques (Macaca mulatta) through the nasal cavity. Pathological pulmonary changes were successively detected on days 5-60 after virus inoculation. All eight animals showed a transient fever 2-3 days after inoculation. Immunological, molecular biological, and pathological studies support the establishment of this SARS animal model. Firstly, SARS-CoV-specific IgGs were detected in the sera of macaques from 11 to 60 days after inoculation. Secondly, SARS-CoV RNA could be detected in pharyngeal swab samples using nested RT-PCR in all infected animals from 5 days after virus inoculation. Finally, histopathological changes of interstitial pneumonia were found in the lungs during the 60 days after viral inoculation: these changes were less marked at later time points, indicating that an active healing process together with resolution of an acute inflammatory response was taking place in these animals. This animal model should provide insight into the mechanisms of SARS-CoV-related pulmonary disease and greatly facilitate the development of vaccines and therapeutics against SARS.
The Journal of Pathology 08/2005; 206(3):251-9. · 6.32 Impact Factor
-
Jun Gao,
Yusheng Wei,
Yue Huang, Depei Liu,
Guang Liu,
Min Wu,
Lin Wu,
Qingjun Zhang,
Zhuqin Zhang,
Ran Zhang,
Chihchuan Liang
[show abstract]
[hide abstract]
ABSTRACT: The apoAI/CIII/AIV gene cluster is involved in lipid metabolism and has a complex pattern of gene expression modulated by a common regulatory element, the apoCIII enhancer. A new member of this cluster, apolipoprotein (apo) AV, has recently been discovered as a novel modifier in triglyceride metabolism. To determine the expression of all four apo genes in combination and, most importantly, whether the transcription of apoAV is coregulated by the apoCIII enhancer in the cluster, we generated an intact transgenic line carrying the 116-kb human apoAI/CIII/AIV/AV gene cluster and a mutant transgenic line in which the apoCIII enhancer was deleted from the 116-kb structure. We demonstrated that the apoCIII enhancer regulated hepatic and intestinal apoAI, apoCIII, and apoAIV expression; however, it did not direct the newly identified apoAV in the cluster. Furthermore, human apo genes displayed integrated position-independent expression and a closer approximation of copy number-dependent expression in the intact transgenic mice. Because apoCIII and apoAV play opposite roles in triglyceride homeostasis, we analyzed the lipid profiles in our transgenic mice to assess the effects of human apoAI gene cluster expression on lipid metabolism. The triglyceride level was elevated in intact transgenic mice but decreased in mutant ones compared with nontransgenic mice. In addition, the expression of human apoAI and apoAIV elevated high density lipoprotein cholesterol in transgenic mice fed an atherogenic diet. In conclusion, our studies with human apoAI/CIII/AIV/AV gene cluster transgenic models showed that the apoCIII enhancer regulated expression of apoAI, apo-CIII, and apoAIV but not apoAV in vivo and showed the influences of expression of the entire cluster on lipid metabolism.
Journal of Biological Chemistry 05/2005; 280(13):12559-66. · 4.77 Impact Factor
