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Yang H.,Capital Medical University | Zeng X.-J.,Capital Medical University | Wang H.-X.,Capital Medical University | Zhang L.-K.,Capital Medical University | And 5 more authors.
Peptides | Year: 2011

Angiotensin II (Ang II) is an important regulator of cardiac function and injury in hypertension. The novel Ang IV peptide/AT4 receptor system has been implicated in several physiological functions and has some effects opposite to those of Ang II. However, little is known about the role of this system in Ang II-induced cardiac injury. Here we studied the effect of Ang IV on Ang II-induced cardiac dysfunction and injury using isolated rat hearts, neonatal cardiomyocytes and cardiac fibroblasts. We found that Ang IV significantly improved Ang II-induced cardiac dysfunction and injury in the isolated heart in response to ischemia/reperfusion (I/R). Moreover, Ang IV inhibited Ang II-induced cardiac cell apoptosis, cardiomyocyte hypertrophy, and proliferation and collagen synthesis of cardiac fibroblasts; these effects were mediated through the AT4 receptor as confirmed by siRNA knockdown. These findings suggest that Ang IV may have a protective effect on Ang II-induced cardiac injury and dysfunction and may be a novel therapeutic target for hypertensive heart disease. © 2011 Elsevier Inc. All rights reserved. Source


Zheng Y.-H.,Peking Union Medical Hospital | Tian C.,Capital Medical University | Meng Y.,Capital Medical University | Qin Y.-W.,Capital Medical University | And 3 more authors.
Journal of Cellular Physiology | Year: 2012

Osteopontin (OPN) exerts pro-inflammatory effect and is associated with the development of abdominal aortic aneurysm (AAA). However, the molecular mechanism underlying this association remains obscure. In the present study, we compared gene expression profiles of AAA tissues using microarray assay, and found that OPN was the highest expressed gene (>125-fold). Furthermore, the expression of LC3 protein and autophagy-related genes including Atg4b, Beclin1/Atg6, Bnip3, and Vps34 was markedly upregulated in AAA tissues. To investigate the ability of OPN to stimulate autophagy as a potential mechanism involved in the pathogenesis of this disease, we treated vascular smooth muscle cells (SMCs) with OPN, and found that OPN significantly increased the formation of autophagosomes, expression of autophagy-related genes and cell death, whereas blocking the signal by anti-OPN antibody markedly inhibited OPN-induced autophagy and SMC death. Furthermore, inhibition of integrin/CD44 and p38 MAPK signaling pathways markedly abrogated the biological effects of OPN on SMCs. These data for the first time demonstrate that OPN sitmulates autophagy directly through integrin/CD44 and p38 MAPK-mediated pathways in SMCs. Thus, inhibition of OPN-induced autophagy might be a potential therapeutic target in the treatment of AAA disease. © 2011 Wiley Periodicals, Inc. Source


Zhang Y.,Peking Union Medical College | Kang Y.-M.,Xian Jiaotong University | Tian C.,Capital Medical University | Zeng Y.,Peking Union Medical Hospital | And 4 more authors.
PLoS ONE | Year: 2011

Background: Cardiac cell death and generation of oxidative stress contribute to doxorubicin (DOX)-induced cardiac dysfunction. E3 ligase Nrdp1 plays a critical role in the regulation of cell apoptosis, inflammation and production of reactive oxygen species (ROS), which may contribute to heart failure. However, the role of Nrdp1 in DOX-induced cardiac injury remains to be determined. Methods and Results: We examined the effect of Nrdp1 overexpression with DOX treatment in rat neonatal cardiomyocytes and mouse heart tissue. Cardiomyocytes were infected with adenovirus containing GFP (Ad-GFP), Nrdp1 wild-type (Ad-Nrdp1) or the dominant-negative form of Nrdp1 (Ad-Dn-Nrdp1), then treated with DOX for 24 hr. DOX treatment increased cell death and apoptosis, with Ad-Nrdp1 infection enhancing these actions but Ad-Dn-Nrdp1 infection attenuating these effects. Furthermore, 5 days after a single injection of DOX (20 mg/kg, intraperitoneally), Nrdp1 transgenic mice (TG) showed decreased cardiac function and increased apoptosis, autophagy and oxidative stress as compared with wild-type (WT) mice (P<0.01). Survival rate was significantly lower in Nrdp1 TG mice than in WT mice 10 days after DOX injection (P<0.01). Conclusions/Significance: These results were associated with decreased activation of Akt, extracellular signal-regulated kinase 1/2 (ERK1/2) and signal transducer and activator of transcription 3 (STAT3) signaling pathways. Nrdp1 may be a key mediator in the development of cardiac dysfunction after DOX treatment and associated with inhibition of Akt, ERK1/2 and STAT3. Nrdp1 may be a new therapeutic target in protecting against the cardiotoxic effects of DOX. © 2011 Zhang et al. Source


Yang D.,Capital Medical University | Tian C.,Capital Medical University | Liu J.,Capital Medical University | Zheng Y.-H.,Peking Union Medical Hospital | Li H.-H.,Capital Medical University
Cellular Physiology and Biochemistry | Year: 2010

Background: Mild hypothermia (32-34°C) improves resistance to ischemia-reperfusion (I/R) injury. However, the mechanisms by which it affects human cellular function are not fully elucidated. To further test for hypothermic modulation of global biological processes, we used DNA microarray technique to detect the overall gene expression profile. Methods: Human umbilical endothelial cells (HUVECs) were incubated under control condition (37°C) or mild hypothermia (33°C) for 2 hours after stimulated ischemia. Detection of differentially expressed genes was performed with Affymetrix U133 plus 2.0 arrays and PARTEK software. We used DAVID and KEGG Pathways database to identify global trends in gene expression data. Results: Our analysis has identified numerous interesting genes and processes that are differentially presented in hypothermic group when compared with normothermic control. The cell cycle was the most prominent process; several genes involved in cell apoptosis and proliferation displayed significantly differential expression; lower transcriptional level was observed for genes involved in chemokine and cell adhesion processes; genes associated with activity of transmembrane transporter and lipase were also under-expressed. Conclusion: Our data indicated that mild hypothermia altered endothelial expression pattern under the condition of I/R, preferably through varying the expression of genes associated with cell cycle, apoptosis, proliferation, and inflammatory response. Copyright © 2010 S. Karger AG, Basel. Source


Chai Y.,Wesley Neurology Clinic in Memphis | Chai Y.,University of Tennessee Health Science Center | Bertorini T.E.,Wesley Neurology Clinic in Memphis | Bertorini T.E.,University of Tennessee Health Science Center | And 2 more authors.
Neuromuscular Disorders | Year: 2011

Dermatomyositis is an autoimmune disorder that causes proximal muscle weakness and skin changes which include generalized erythema, heliotrope rash and/or Gottron's papules. Generalized or limb edema is an uncommon manifestation of dermatomyositis. Here, we report four cases who presented with generalized or limb edema, proximal muscle weakness, erythematous skin rash and/or dysphagia. Muscle biopsy revealed perifascicular fiber atrophy, a characteristic finding of dermatomyositis. The absence of other causes indicated that the generalized or limb edema was caused by dermatomyositis. None of our patients showed significant improvement with steroids alone, and more aggressive immunotherapy eventually resolved the edema. We concluded that generalized or limb edema may be a hallmark of a severe form of dermatomyositis and requires prompt and aggressive therapies. © 2011 Elsevier B.V. Source

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