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PubMed | Beijing Institute of Heart, Stanford University, Zhengzhou University and Peking University
Type: Journal Article | Journal: Oncotarget | Year: 2016

The expression of intermediate filament Nestin is necessary for the neural progenitor cells (NPCs) to maintain stemness, but the underlying cellular and molecular mechanism remains unclear. In this study, we demonstrated that Nestin is required for the self-renew of NPCs through activating MAPK and EGFR pathways. Knockdown of Nestin by shRNA inhibited cell cycle progression and proliferation in mouse NPCs. Moreover, suppression of Nestin reduced expression of the epidermal growth factor receptor (EGFR) in NPCs and inhibited the mitogenic effects of EGF on these cells. Treatment of NPCs with p38-MAPK inhibitor PD169316 reversed cell cycle arrest caused by the knockdown of Nestin. Our findings indicate that Nestin promotes NPC proliferation via p38-MAPK and EGFR pathways, and reveals the necessity of these pathways in NPCs self-renewal.

Moran A.,Columbia University | Gu D.,Fu Wai Hospital of the Chinese | Gu D.,National Center for Cardiovascular Diseases | Gu D.,Fu Wai Hospital | And 14 more authors.
Circulation: Cardiovascular Quality and Outcomes | Year: 2010

Background-The relative effects of individual and combined risk factor trends on future cardiovascular disease in China have not been quantified in detail. Methods and Results-Future risk factor trends in China were projected based on prior trends. Cardiovascular disease (coronary heart disease and stroke) in adults ages 35 to 84 years was projected from 2010 to 2030 using the Coronary Heart Disease Policy Model-China, a Markov computer simulation model. With risk factor levels held constant, projected annual cardiovascular events increased by >50% between 2010 and 2030 based on population aging and growth alone. Projected trends in blood pressure, total cholesterol, diabetes (increases), and active smoking (decline) would increase annual cardiovascular disease events by an additional 23%, an increase of approximately 21.3 million cardiovascular events and 7.7 million cardiovascular deaths over 2010 to 2030. Aggressively reducing active smoking in Chinese men to 20% prevalence in 2020 and 10% prevalence in 2030 or reducing mean systolic blood pressure by 3.8 mm Hg in men and women would counteract adverse trends in other risk factors by preventing cardiovascular events and 2.9 to 5.7 million total deaths over 2 decades. Conclusions-Aging and population growth will increase cardiovascular disease by more than a half over the coming 20 years, and projected unfavorable trends in blood pressure, total cholesterol, diabetes, and body mass index may accelerate the epidemic. National policy aimed at controlling blood pressure, smoking, and other risk factors would counteract the expected future cardiovascular disease epidemic in China. © 2009 American Heart Association, Inc.

Zheng Y.-H.,Peking Union Medical Hospital | Li F.-D.,Peking Union Medical Hospital | Tian C.,Capital Medical University | Tian C.,Beijing Institute of Heart | And 5 more authors.
PLoS ONE | Year: 2013

Abdominal aortic aneurysm (AAA) is a life-threatening aortic disease in the elderly. Activation of Notch1 pathway plays a critical role in the development of AAA, but the underlying mechanisms remain poorly understood. In the present study, we explored the mechanisms by which Notch1 activation regulates angiotensin II (Ang II)-induced AAA formation and evaluated the therapeutic potential of a new Notch γ-secretase inhibitor, dibenzazepine (DBZ), for the treatment of AAA. Apolipoprotein E knockout (Apo E-/-) mice infused for 4 weeks with Ang II (1000 ng/kg/min, IP) using osmotic mini-pumps were received an intraperitoneal injection of either vehicle or 1 mg/kg/d DBZ. Notch1 signaling was activated in AAA tissue from both Ang II-infused Apo E -/- mice and human undergoing AAA repair in vivo, with increased expression of Notch intracellular domain (NICD) and its target gene Hes1, and this effect was effectively blocked by DBZ. Moreover, infusion of Ang II markedly increased the incidence and severity of AAA in Apo E-/- mice. In contrast, inhibition of Notch activation by DBZ prevented AAA formation in vivo. Furthermore, DBZ markedly prevented Ang II-stimulated accumulation of macrophages and CD4+ T cells, and ERK-mediated angiogenesis, simultaneously reversed Th2 response, in vivo. In conclusion, these findings provide new insight into the multiple mechanisms of Notch signaling involved in AAA formation and suggest that γ-secretase inhibitor DBZ might be a novel therapeutic drug for treating AAAS. © 2013 Zheng et al.

Wang Z.,Capital Medical University | Liu Y.,Capital Medical University | Liu J.,Capital Medical University | Liu K.,Capital Medical University | And 3 more authors.
Journal of Atherosclerosis and Thrombosis | Year: 2011

Aim: Hyperplasia suppressor gene/mitofusion-2 (HSG/Mfn2) is a hyperplasia suppressor gene and an essential component of mitochondrial fusion machinery; however, the association between the single nucleotide polymorphism (SNP) of HSG/Mfn2 and hypertension is unclear. Methods: In this study, 542 normotensive subjects (NT group) and 539 hypertensive patients (EH group) were screened for an association study between HSG/Mfn2 and hypertension. Results: The results showed that the genotype distribution and allelic frequency of rs873457, rs2336384, rs1474868, rs4846085 and rs2236055 were significantly different (P<0.05 for all) between EH and NT groups, although those of rs4240897 and rs873458 were not. When comparing the dominant model, significant differences still existed (P<0.05 for all). The allelic frequency of rs4240897 was also slightly different between EH and NT groups (P = 0.047). When subgrouped by sex, the genotype distribution and allelic frequency of all the SNPs (except rs873458) were significantly different in male (P<0.05 for all) but not in female groups. For all the SNPs, only the allelic frequency of rs4240897 was obviously different in female NT and EH groups (P<0.01). Logistic regression showed that body mass index and rs873457 were closely associated with BP after adjusting for age. The frequency of the C-G-A-A-A-C-C haplotype was significantly higher in essential hypertensive patients versus control individuals, both in the entire population, in male or female groups (P<0.01 for all). As for other haplotypes, most were only significantly different in the entire population and male subjects. Conclusion: The genetic variations of HSG/Mfn2 may be associated with hypertension in male Chinese.

Wang Z.-H.,Capital Medical University | Wang Z.-H.,Beijing Institute of Heart | Li Y.-F.,Capital Medical University | Li Y.-F.,Beijing Institute of Heart | And 2 more authors.
Acta Pharmacologica Sinica | Year: 2013

Aim: To examine the effects of β3 -adrenoceptor (β3 -AR) activation on atherosclerotic plaque development in ApoE-/- mice. Methods: Thirty six week-old male ApoE-/- mice on a high-fat diet were treated with atorvastatin (10 mg·kg -1 ·d-1, po), BRL37344 (β3-AR agonist, 1.65 or 3.30 μg/kg, ip, twice a week) or SR52390A (β3-AR antagonist, 50 μg/kg, ip, twice a week) for 12 weeks. Wild-type C57BL/6J mice receiving a normal diet were taken as healthy controls. At the end of the treatments, serum levels of triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), non-high density lipoprotein cholesterol (nHDL-C), glucose and insulin were measured. The thoracic aortas were dissected out, the area of atherosclerotic plaques and extent of fibrosis in the plaques were examined using HE and Masson's trichome staining, respectively. Results: Compared to wild-type mice, ApoE-/- mice fed on a high-fat diet exhibited prominent hyperlipidemia and insulin resistance, associated with large area of atherosclerotic plaques and great extent of fibrosis in aortas. Atorvastatin significantly decreased the serum levels of TC and nHDL-C, and reduced the plaque area and collagen content in aortas. BRL37344 significantly decreased the serum levels of TG, TC, nHDL-C, glucose and insulin, and increased HDL-C and the insulin sensitivity, and dose-dependently reduced the plaque area and collagen content in aortas. SR52390A treatment did not affect any parameters studied. Conclusion: The β3-AR agonist impedes the progression of atherosclerosis in ApoE-/- mice, through improvement of the lipid and glucose profiles. © 2013 CPS and SIMM.

To explore the 15-years change in fasting TG level and the accumulative incidence of type 2 diabetes mellitus (T2DM) from 1992 to 2007, and to assess the association between the change in TG level and the accumulative onset risk of T2DM. A total of 11 387 subjects aged 35 - 64 years were recruited from 6 provinces in China in the baseline survey in 1992, and were followed-up for cardiovascular disease till 2007. In 2007, 9184 subjects were successfully followed-up and 5966 subjects entered into the second examination. Totally 5408 participants, who were free of diabetes at baseline and had complete information for both check ups, were included in this analysis. Fasting TG levels were categorized into three groups: < 1.70 mmol/L, 1.70 - 2.25 mmol/L and ≥ 2.26 mmol/L. The association between 15-years change in TG level and the accumulative onset risk of T2DM was assessed by logistic regression analysis. In 1992, the mean level of TG was 1.49 mmol/L in male and 1.26 mmol/L in female. During the 15 years, TG levels increased by 0.25 mmol/L and 0.53 mmol/L in male and female, respectively. The prevalence of elevated TG (< 1.70 mmol/L) increased from 23.4% in 1992 to 39.0% in 2007. The 15-year accumulative incidence of diabetes was 13.9% in male and 11.8% in female. The incidence rates were 10.5%, 16.2% and 26.6% for TG levels of < 1.70 mmol/L, 1.70 - 2.25 mmol/L and ≥ 2.26 mmol/L, respectively. Multivariate logistic regression analysis showed that the baseline TG level was significantly associated with the onset risk of diabetes after adjustment for other cardiovascular risk factors. At any given baseline TG level, the onset risk of diabetes increased with the TG levels in the second examination in 2007. After adjusting other risk factors, participants with the highest categories of both baseline and follow-up TG levels had 2.1 folds higher accumulative onset risk of diabetes (RR = 3.39, 95%CI 2.49 - 4.61) than those with the lowest categories of both baseline and follow-up TG levels. Baseline TG level is independently associated with diabetes onset risk, and the change of TG level in a 15-year interval predicts the onset risk of diabetes beyond the baseline TG level.

Zhang J.,Capital Medical University | Zhang J.,Beijing Institute of Heart | Xiao Z.,Capital Medical University | Xiao Z.,Beijing Institute of Heart | And 8 more authors.
Journal of Immunology | Year: 2014

Inflammatory microenvironments play a key role in skeletal muscle regeneration. The infiltration of CD8 T cells into injured muscle has been reported. However, the role of CD8 T cells during skeletal muscle regeneration remains unclear. In this study, we used cardiotoxin-Induced mouse skeletal muscle injury/regeneration model to investigate the role of CD8 T cells. Muscle regeneration was impaired and matrix deposit was increased in CD8α -Deficient mice compared with wild-Type (WT) mice whose CD8 T cells were infiltrated into damaged muscle after cardiotoxin injection. Adoptive transfer of CD8 T cells to CD8α-Deficient mice improved muscle regeneration and inhibited matrix remodeling. Compared with WT mice, CD8α deficiency limited the recruitment of Gr1high macrophages (MPs) into muscle, resulting in the reduction of satellite cell number. The expression of MCP-1 (MCP-1/CCL2), which regulates the migration of Gr1high MPs, was reduced in CD8α-Deficient mice compared with WT mice. Coculture CD8 T cells with MPs promoted MCP-1 secretion. The i.m. injection of MCP-1 markedly promoted the recruitment of Gr1high MPs and improved muscle regeneration in CD8α-Deficient mice. We conclude that CD8 T cells are involved in skeletal muscle regeneration by regulating the secretion of MCP-1 to recruit Gr1high MPs, which facilitate myoblast proliferation. © 2014 by The American Association of Immunologists, Inc.

Lu Y.H.,Beijing Institute of Heart
Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases | Year: 2011

The purpose of the present study aimed to evaluate the left ventricular systolic function and diastolic filling characteristics in pulmonary thromboembolism (PTE). A total of 102 patients with PTE, including acute or acute on chronic PTE, were consecutively recruited from January of 2006 to December of 2010. The patients [53 males and 49 females; age (64 ± 14) years, range 23 - 85 years] all underwent Doppler echocardiographic assessment before thrombolytic therapy or within 24 h of hospital admission to the emergency intensive care unit of Beijing Anzhen hospital. Fifty-one age- and gender-matched healthy controls [29 males and 22 females; age (61 ± 9) years, range 31-79 years] were recruited from the Health Center. One hundred and sixty age- and gender-matched coronary artery disease (CAD) patients [90 males and 70 females, age (61 ± 11) years, range 29 - 81 years] with positive coronary artery angiography were also included as controls during the period of January of 2009 through December of 2010. Trans-thoracic Doppler echocardiography was used to assess the trans-mitral filling pattern and left ventricular systolic function in all the subjects. The trans-mitral blood flow peak of early (E) wave less than that of the auricular (A) wave, or the ratio of E/A greater than 2, were defined as abnormal left ventricular diastolic filling. Left ventricular ejection fraction (LVEF) greater than 50% was defined as preserved systolic function. The prevalence of abnormal left ventricular diastolic filling and systolic dysfunction were compared with Chi-square test between the PTE patients and the 2 control groups. Tricuspid regurgitation was identified in 72.5% (74/102) of the 102 PTE patients, abnormal left ventricular diastolic filling was detected in 77.5% (79/102) of the PTE patients, and 95.1% (97/102) of the PTE patients had preserved left ventricular systolic function with LVEF of > 50%. Further analysis revealed that the abnormal left ventricular diastolic filling was more frequent in PTE patients with CAD and/or hypertension than in other PTE patients (χ(2) = 5.280, P < 0.05), 85.2% (52/61) and 65.9% (27/41), respectively. Overall, the prevalence of abnormal left ventricular diastolic filling in PTE patients (77.5%, 79/102) was significantly higher than that in healthy controls (25.5%, 13/51, χ(2) = 38.300, P < 0.001), and the fraction of left ventricular systolic dysfunction was significantly lower (4.9%, 5/102) than that in CAD patients (29.4%, 47/160, χ(2) = 23.450, P < 0.001). In the PTE patients with neither CAD nor hypertension, the abnormal left ventricular diastolic filling was still more frequent (65.9%, 27/41) than in healthy controls (25.5%, 13/51, χ(2) = 15.070, P < 0.001), but there was no significant difference when compared with that in CAD patients (73.8%, 118/160, χ(2) = 1.013, P > 0.05). The results strongly suggest that abnormal left ventricular diastolic filling constitutes a common and a major form of left ventricular dysfunction in PTE patients. It indicates that enhanced alertness to and early identification of abnormal left ventricular diastolic filling may play an important role in improving prognosis for PTE.

Wang L.,Capital Medical University | Wang L.,Beijing Institute of Heart | Li Y.-L.,Capital Medical University | Li Y.-L.,Beijing Institute of Heart | And 11 more authors.
Cardiovascular Research | Year: 2014

AimsToll-like receptor 2 (TLR2) is an important player in innate immunity, and recent studies have identified TLR2 as a critical mediator in cardiovascular diseases. Here, we investigated the involvement of TLR2 in angiotensin (Ang) II-induced cardiac fibrosis and the underlying mechanisms.Methods and resultsTLR2 knockout (TLR2 KO) mice (B6.129-Tlr2tm1Kir/) or wild-type (WT) mice (C57BL/6) treated with neutralizing anti-TLR2 antibody (T2.5) were used. The expression of TLR2 mRNA and protein in the heart was significantly up-regulated on days 1, 3, and 7 after Ang II infusion (1500 ng/kg/min). Enhanced expression of TLR2 was mainly detected in macrophages and neutrophils that had infiltrated into the heart. Both knockout of TLR2 and inhibition of TLR2 by neutralizing antibody ameliorated cardiac fibrosis induced by Ang II. This improvement was associated with a reduction in the infiltration of inflammatory cells, especially macrophages, the production of inflammatory cytokines, chemokines, and the activation of nuclear factor-κB. Bone marrow transplantation experiments between WT and TLR2 KO mice revealed that Ang II-induced cardiac fibrosis is mainly mediated by bone marrow-derived inflammatory cells. Mechanically, the deficiency of TLR2 inhibits macrophage-dependent cardiac fibroblast activation through TGFβ/Smad2/3 pathway.ConclusionInhibition of TLR2 protects against Ang II-induced cardiac fibrosis by attenuating macrophage recruitment and the inflammatory response in the heart and may be a novel potential therapeutic target for hypertensive heart disease. © 2013 The Author.

Xin Y.,Beijing Institute of Heart
Zhongguo shi yan xue ye xue za zhi / Zhongguo bing li sheng li xue hui = Journal of experimental hematology / Chinese Association of Pathophysiology | Year: 2013

This study was aimed to evaluate an effective and stable method for obtaining mesenchymal stem cells (MSC) and endothelial progenitor cells (EPC) from the rabbit bone marrow and to investigate the biological characteristics of MSC and EPC. Mononuclear cells were obtained from rabbit bone marrow using density gradient method, and were differentially adhered to the cell culture plate enclosed with fibronectin. Then, MSC and EPC were amplified with EGB-2MV medium. Trypan blue method was used to test the passage survival rate. Growth curve, MTT and DNA cycle were used to evaluate the proliferation ability of MSC and EPC. MSC were identified with induced differentiation into the osteoblasts and adipocytes, and their immune phenotype was detected by flow cytometry (FCM). EPC were characterized by the special digestion of Dil-ac-LDL, FITC-UEA-I, and the conjunction with CD133, VEGFR2/KDR and CD34, their purity was also calculated. The results indicated that the colony was obviously formed when the mononuclear cells were cultured for 24 hours and, 80% of the cells became long spindle and integrated at d 8. Cells, which were adhered for twice, were cultured with EGM-2MV medium, began to extend at d 3, and became strip-shaped and integrated for about 80% at d 8. Passage survival rates were more than 90% for both cells, and after passage 2 the growth curve was like "S". Optical density was changed obviously when the cells were cultured for 3 - 5 d, but there were no significant difference of cell cycles between MSC and EPC, which G0-G1 was (93.32 ± 1.65)% and (93.05 ± 1.95)% respectively. Positive rates were (99.7 ± 1.12)%, (99.1 ± 2.33)%, (4.8 ± 0.38)%, (6.8 ± 0.49)% and (0.4 ± 0.08)% for CD90, CD44, CD14, CD45 and CD79a respectively. MSC were identified by induced differentiation into osteoblasts and adipocytes. Positive rates of the EPC, which were adhered for twice and passaged 2, were (82.1 ± 3.4)% for fluorescent staining of Dil-ac-LDL and FITC-UEA-I, and (74.2 ± 3.2)%, (64.7 ± 4.3)% and (43.5 ± 1.5)% for CD133, VEGFR2/KDR and CD34 respectively. It is concluded that high-purity MSC can be obtained with density gradient and differential adhesion method, and high-proliferation EPC can be cultured with EGM-2MV medium in cell plates enclosed with fibronectin, so they may become the optimal seed cells for tissue engineering study.

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