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1. Inhibition of TGF-β1 by eNOS gene transfer provides cardiac protection after myocardial infarction. J Biomed Res, 2010; 24(2):145-152 Wei Qin, Xin Chen, Peisheng Liu Department of Cardiothoracic Surgery, Nanjing First Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210006, China. Abstract: Objective: Endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) have been implicated in protection against myocardial ischemia injury. This study was designed to explore a new method of therapy for myocardial injury by eNOS gene transfection. Methods: A rat model of myocardial infarction (MI) was established by left anterior descending (LAD) coronary artery ligation. eNOS gene in an adenovirus vector was delivered locally into the rat heart and hemodynamic parameters were examined after 3 weeks, Matrix metalloproteinase-2 and 9 (MMP-2, MMP-9) mRNA were measured by reverse transcription polymerase chain reaction (RT-PCR), and the protein levels of eNOS, caspase-3, and transforming growth factor β1 (TGF-β1) were determined by western blot assay. Results: eNOS gene transfer significantly reduced cardiomyocyte apoptosis and improved cardiac function. In addition, eNOS significantly reduced the mRNA levels of MMP-2 and MMP-9. In the eNOS gene transfected group, the activation of caspase-3 and TGF-β1 were decreased. However, the protection was reversed by administration of the NOS inhibitor, N(ω)-nitro-l-arginine methyl ester (L-NAME). Conclusion: These results demonstrate that the eNOS provides cardiac protection after myocardial infarction injury through inhibition of cardiac apoptosis and collagen deposition, and suppression of TGF-β1. http://www.jbr-pub.org/ch/reader/view_abstract.aspx?file_no=jbr100208&flag=1 2. Vascular smooth muscle cell differentiation–2010. J Biomed Res, 2010; 24(3):169-180 Joseph M. Miano Aab Cardiovascular Research Institute, University of Rochester School of Medicine & Dentistry, New York 14642, USA. Abstract: Vascular smooth muscle cells have attracted considerable interest as a model for a flexible program of gene expression. This cell type arises throughout the embryo body plan via poorly understood signaling cascades that direct the expression of transcription factors and microRNAs which, in turn, orchestrate the activation of contractile genes collectively defining this cell lineage. The discovery of myocardin and its close association with serum response factor has represented a major break-through for the molecular understanding of vascular smooth muscle cell differentiation. Retinoids have been shown to improve the outcome of vessel wall remodeling following injury and have provided further insights into the molecular circuitry that defines the vascular smooth muscle cell phenotype. This review summarizes the progress to date in each of these areas of vascular smooth muscle cell biology. http://www.jbr-pub.org/ch/reader/view_abstract.aspx?file_no=jbr100301&flag=1 3. HGF percutaneous endocardial injection induces cardiomyocyte proliferation and rescues cardiac function in pigs. J Biomed Res, 2010; 24(3):198-206 Zhengxian Taoa, Bo Chena, Yingming Zhaoa, Hongwu Chena, Liansheng Wanga, Yonghong Yonga, Kejiang Caoa, Qifeng Yub, Danian Keb, Hua Wangc, Zuze Wuc, Zhijian Yanga a Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China; b MicroPort Medical (Shanghai) CO., Ltd., Shanghai 201203, China; c Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850, China. Abstract: Objective: To investigate the effect of cardiomyocyte proliferation induced by human hepatocyte growth factor (HGF) in pigs with chronic myocardial infarction (CMI). Methods: A steerable, deflectable 7F catheter incorporating a 27-guage needle was advanced percutaneously to the left ventricular myocardium of 18 pigs with CMI. Pigs were randomized (1:1:1) to receive adenoviral vector HGF (total dose, 1×1010 genome copies), which was administered as five injections into the infarcted myocardium (total, 1.0 mL), or saline, or Ad-null (control groups). Injections were guided by Ensite NavX left ventricular electroanatomical mapping. HGF and cyclin proteins were detected by western blot and immunoprecipitation analysis. Histological and immunohistochemical analysis determined proliferating cardiomyocytes. Myocardial perfusion and cardiac function were estimated by Gated-Single Photon Emission Computed Tomography (G-SPECT). Results: Western blot analyses showed that HGF were predominantly expressed in the infarct core and border in the myocardium of the infarcted heart. G-SPECT analysis indicated that the HGF group had better cardiac function and myocardial perfusion four weeks after the injection of Ad-HGF than before the injection of Ad-HGF. After treatment there were more proliferating cardiomyocytes in the HGF group compared to either of the control groups. Furthermore, the HGF group myocardial samples expressed higher levels of p-Akt, cyclin A, cyclin E, cyclin D1, cdk2, cdk4 than those in the control groups. Conclusion: The over-expression of HGF activates pro-survival pathways, induces cardiomyocyte proliferation, and improves the perfusion and function of the porcine CMI heart. http://www.jbr-pub.org/ch/reader/view_abstract.aspx?file_no=jbr100304&flag=1 4. Arrhythmogenic properties of dismantling cadherin-mediated adhesion in murine hearts. J Biomed Res, 2010; 24(4):292-300 Hongjun Zhu, Hegui Wang, Xiwen Zhang, Xiaofeng Hou, Kejiang Cao, Jiangang Zou Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China. Abstract: Objective: To evaluate the arrhythmogenic effects of dismantling cadherin-mediated adhesion by recombinant mouse aminopeptidase N (rmAPN) in murine hearts. Methods: rmAPN was incubated with cultured neonatal rat cardiomyocytes as well as being infused in adult mice. The cell-cell connections were immunolabelled and ob-served by laser confocal microscopy. Disruption of the N-terminal of N-cadherin (N-cad) was detected by western blot and quantitative immunofluorescence. The risk of inducible ventricular tachyarrhythmia was evaluated in mice by an electrophysiological study. Results: Disrupted cell-cell contact was observed in cultured neonatal rat cardiomyocytes in response to 30-40 ng/μL rmAPN. Loss of the N-terminal in N-cad and altered distribution of connexin 43 (Cx43) were observed in hearts from rmAPN-infused mice. In addition, a reduction of phosphorylated Cx43 was also detected concomitant with redistribution of Cx43. Electrophysiological studies of rmAPN-infused mice showed prolonged QRS duration and increased inducibility of ventricular tachycardias. Conclusion: Disruption of N-cad by rmAPN contributes to gap junction remodeling and may elicit arrhythmogenic effects. The disorder of adherent junctions by proteolytic enzymes may play an important role in arrhythmogenic mechanisms in correlated diseases. http://www.jbr-pub.org/ch/reader/view_abstract.aspx?file_no=JBR100406&flag=1 5. Activation of calcium-sensing receptors is associated with apoptosis in a model of simulated cardiomyocytes ischemia/reperfusion. J Biomed Res, 2010; 24(4):301-307 Ling Yana, Tiebing Zhua, Tingting Suna, Liansheng Wanga, Shiyang Panb, Zhengxian Taoc, Zhijian Yanga, Kejiang Caoa a Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China; b Department of Clinical Key Laboratory, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China; c Department of Biochemistry, Nanjing Medical University, Nanjing, Jiangsu 210029, China. Abstract: Objective: Calcium-sensing receptors (CaSRs) are G-protein coupled receptors which maintain systemic calcium homeostasis and participate in hormone secretion, activation of ion channels, cell apoptosis, proliferation, and differentiation. Previous studies have shown that CaSRs induce apoptosis in isolated adult rat heart and in normal neonatal rat cardiomyocytes by G-protein-PLC-IP3 signaling transduction. However, little knowledge is presently available concerning the role of CaSRs in the apoptosis induced by ischemia and reperfusion in neo-natal cardiomyocytes. Methods: Primary neonatal rat ventricular cardiomyocytes were incubated in ischemia-mimetic solution for 2 h, and then re-incubated in normal culture medium for 24 h to establish a model of simulated ischemia/reperfusion (I/R). Cardiomyocyte apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). The expression of CaSRs mRNA was detected by real-time reverse transcription polymerase chain reaction (RT-PCR). In addition, the expressions of caspase-3 and Bcl-2 were analyzed by western blot. Results: The simulated I/R enhanced the expression of CaSRs and cardiomyocyte apoptosis. GdCl3, a specific activator of CaSRs, further increased the expression of CaSRs and cardiomyocyte apoptosis, along with up-regulation of caspase-3 and down-regulation of Bcl-2. Conclusion: CaSRs are associated with I/R injury and apoptosis in neonatal rat ventricular cardiomyocytes via suppressing Bcl-2 and promoting caspase-3 expression. http://www.jbr-pub.org/ch/reader/view_abstract.aspx?file_no=JBR100407&flag=1 6. The cardioprotection induced by lipopolysaccharide involves phosphoinositide 3-kinase/Akt and high mobility group box 1 pathways. J Biomed Res, 2010; 24(4):324-331 Xiang Liua, Yijiang Chena, Yanhu Wua, Tuanzhu Hab, Chuanfu Lib a Department of Cardiothoracic Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China; b Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA. Abstract: Objective: The mechanisms by which lipopolysaccharide (LPS) pretreatment induces cardioprotection following ischaemia/reperfusion (I/R) have not been fully elucidated. We hypothesized that activation of phosphoinositide 3-kinase (PI3K)/Akt and high mobility group box 1 (HMGBx1) signaling plays an important role in LPS-induced cardioprotection. Methods: In in vivo experiments, age- and weight- matched male C57BL/10Sc wild type mice were pretreated with LPS before ligation of the left anterior descending coronary followed by reperfusion. Infarction size was examined by triphenyltetrazolium chloride (TTC) staining. Akt, phospho-Akt, and HMGBx1 were assessed by immunoblotting with appropriate primary antibodies. In situ cardiac myocyte apoptosis was examined by the TdT-mediated dUTP nick-end labeling (TUNEL) assay. In an in vitro study, rat cardiac myoblasts (H9c2) were subdivided into two groups, and only one was pretreated with LPS. After pretreatment, the cells were transferred into a hypoxic chamber under 0.5% O2. Levels of HMGBx1 were assessed by immunoblot. Results: In the in vivo experiment, pretreatment with LPS reduced the at risk infarct size by 70.6% and the left ventricle infarct size by 64.93% respectively. Pretreatment with LPS also reduced cardiac myocytes apoptosis by 39.1% after ischemia and reperfusion. The mechanisms of LPS induced cardioprotection involved increasing PI3K/Akt activity and decreasing expression of HMGBx1. In the in vitro study, pretreatment with LPS reduced the level of HMGBx1 in H9c2 cell cytoplasm following hypoxia. Conclusion: The results suggest that the cardioprotection following I/R induced by LPS pretreatment involves PI3K/Akt and HMGBx1 pathways. http://www.jbr-pub.org/ch/reader/view_abstract.aspx?file_no=JBR100410&flag=1 7. Retrieval of dislodged coronary stent from left renal artery by gooseneck snare. J Biomed Res, 2010; 24(6):479-482 Chunjian Li, Zhijian Yang, Kejiang Cao Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China. Abstract: A rapamycin-eluting stent was dislodged during attempt of implantation at the proximal right coronary artery, which was found by fluoroscopy to have migrated into the anterior trunk of the left renal artery. We chose a 5 mm diameter Amplatz gooseneck snare and successfully retrieved the lost stent from the lodging vessel. http://www.jbr-pub.org/ch/reader/view_abstract.aspx?file_no=jbr100610&flag=1 8 Gender-based differences in cardiac diseases. J Biomed Res, 2011; 25(2):81-89 Pei-Chi Yang, Colleen E. Clancy Department of Pharmacology, University of California Davis. Davis, CA 96516-5270, USA. Abstract: It has been observed that the incidence of heart failure and Brugada syndrome are higher in men, while women are more likely to have QT interval prolongation and develop torsades de pointes (TdP). Over the past decade, new studies have improved our understanding of the mechanisms of abnormal repolarization and the relationship between gender differences in cardiac repolarization and presentation of clinical syndromes. Nevertheless, the causes of gender-based differences in cardiac disease are still not completely clear. This review paper briefly summarized what is currently known about gender differences in heart failure, Brugada syndrome and long QT syndrome from molecular mechanisms to clinical presentations. http://www.jbr-pub.org/ch/reader/view_abstract.aspx?file_no=jbr110201&flag=1 9 TLR2 was overexpressed independent of IL-6 in patients with valvular atrial fibrillation. J Biomed Res, 2011; 25(3):178-184 Jian Wanga, Lei Xuea, Hailong Caoa, Fei Cuia, Ting Daib, Yijiang Chena a Department of Thoracic and Cardiovascular Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China; b Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China. Abstract: Toll-like receptor 2 (TLR2) has recently been shown to be up-regulated in patients with non-valvular atrial fibrillation (AF). The present study was aimed to determine whether the pathogenesis and development of AF is associated with the up-regulation of TLR2. Clinical data and right atrial appendage (RAA) specimens were collected from 20 patients with persisten AF (PeAF), 15 patients with paroxysmal AF (PaAF) and 13 patients with no history of AF undergoing valvular replacement. The results showed that gene expression and protein content of TLR2 were increased in both the AF subgroups, compared with the sinus rhythm (SR) group. Between the two AF subgroups, PaAF had a higher TLR2 level than PeAF. However, no difference in interluekin (IL)-6 content was found among the three groups, and no correlation was found between TLR2 and IL-6 in PeAF patients (r = 0.090, P = 0.706), PaAF patients (r = 0.408, P = 0.131) and AF patients (r = -0.301, P = 0.079). Immunohistochemical analysis revealed that TLR2 was distributed in RAAs of AF patients and confirmed the immunoblotting results. In conclusion, we demonstrated that TLR2 was elevated in AF (especially PaAF) patients with valvular heart disease, further implicating inflammation involved in the pathogenesis and development of AF. http://www.jbr-pub.org/ch/reader/view_abstract.aspx?file_no=jbr110304&flag=1 10 Hypoxic response elements and Tet-On advanced double-controlled systems regulate hVEGF165 and angiopoietin-1 gene expression in vitro. J Biomed Res, 2011; 25(3):204-212 Hao Zhanga, Hongyan Dongb, Bo Jianga, Zheng Wanga, Rui Chena, Zhifeng Zhangb, Zhongming Zhanga a Institute of Cardiovascular Disease, Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu 221002, China; b Center of Biological Research, Xuzhou Medical College, Xuzhou, Jiangsu 221002, China. Abstract: Angiogenesis in ischemic tissue is a complex and multi-gene event. In the study, we constructed hypoxic response elements (HRE) and the Tet-On advanced double-controlled systems and investigated their effects on the expression of hVEGF165 and angiopoietin-1 (Ang-1) genes in rat cardiomyocytes exposed to hypoxia and pharmacologic induction. We infected neonatal rat cardiomyocytes with recombinant rAAV-rtTA-Rs-M2/rAAV-TRE-Tight-Ang-1 and rAAV-9HRE- hVEGF165. Our results indicated that the viral titer was 1×1012 vg /mL and the viral purity exceeded 98%. hVEGF165 expression was induced by hypoxia, but not by normoxia (P < 0.001). Ang-1 expression was evident under doxycycline induction, but undetectable without doxycycline induction (P < 0.001). Immunofluorescence staining showed that positively stained hVEGF165 and Ang-1 protein appeared only under both hypoxia and doxycycline induction. We demonstrate here that HRE and the recombinant Tet-On advanced double gene-controlled systems sensitively regulate the expression of hVEGF165 and Ang-1 genes in an altered oxygen environment and under pharmacological induction in vitro. http://www.jbr-pub.org/ch/reader/view_abstract.aspx?file_no=jbr110308&flag=1 11 Bisoprolol reverses down-regulation of potassium channel proteins in ventricular tissues of rabbits with heart failure. J Biomed Res, 2011; 25(4):274-279 Xi Lia,b,c,d, Tingzhong Wanga,b,c, Ke Hana,b,c, Xiaozhen Zhuoa,b,c, Qun Lua,b,c, Aiqun Maa,b,c a Department of Cardiovascular Medicine, the First Affiliated Hospital of Medical School, Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China; b Key Laboratory of Molecular Cardiology of Shaanxi Province, Xi’an, Shaanxi 710061, China; C Key Laboratory of Environment and Genes Related to Diseases, Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China; d Department of Cardiovascular Medicine, the Second Affiliated Hospital of Medical School, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750001, China. Abstract: Remodeling of ion channels is an important mechanism of arrhythmia induced by heart failure (HF). We investigated the expression of potassium channel encoding genes in the ventricles of rabbit established by volume-overload operation followed with pressure-overload. The reversible effect of these changes with bisoprolol was also evaluated. The HF group exhibited left ventricular enlargement, systolic dysfunction, prolongation of corrected QT interval (QTc), and increased plasma brain natriuretic peptide levels in the HF rabbits. Several potassium channel subunit encoding genes were consistently down-regulated in the HF rabbits. After bisoprolol treatment, heart function was improved significantly and QTc was shortened. Additionally, the mRNA expression of potassium channel subunit genes could be partially reversed. The down-regulated expression of potassium channel subunits Kv4.3, Kv1.4, KvLQT1, minK and Kir 2.1 may contribute to the prolongation of action potential duration in the heart of rabbits induced by volume combined with pressure overload HF. Bisoprolol could partially reverse these down-regulations and improve heart function. http://www.jbr-pub.org/ch/reader/view_abstract.aspx?file_no=jbr110407&flag=1 12 Variants of the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene and risk of ischemic stroke in Han Chinese of eastern China. J Biomed Res, 2011; 25(5):319-327 Gannan Wanga, Yao Wanga, Hao Suna, Weijuan Caoa, Jing Zhanga, Hang Xiaob, Jinsong Zhanga a Emergency Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China; b Laboratory of Neurotoxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029, China. Abstract: Variants of the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene have been suggested to play an important role in the pathogenesis of atherosclerosis and ischemic stroke. This study was aimed to explore the association of ALOX5AP variants with ischemic stroke risk in Han Chinese of eastern China. A total of 690 ischemic stroke cases and 767 controls were recruited. The subjects were further subtyped according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. On the basis of that, two polymorphisms of the ALOX5AP gene (rs10507391 and rs12429692) were determined by TaqMan genotyping assay. In addition, plasma leuko-triene B4 (LTB4) levels were analyzed in these subjects. There was no evidence of association between the two variants of ALOX5AP and the risk of ischemic stroke or its TOAST-subtypes. Haplotype analysis and stratification analysis according to sex, age, body mass index, hypertension, and diabetes also showed negative association. Analysis of LTB4 levels in a subset of cases and controls revealed that LTB4 levels were significantly higher in ischemic stroke cases than in the controls (70.06±14.75 ng/L vs 57.34±10.93 ng/L; P = 0.000) and carriers of the T allele of the rs10507391 variant were associated with higher plasma LTB4 levels (P = 0.000). The present study suggests there is no association of the two polymorphisms in the ALOX5AP gene with ischemic stroke risk in Han Chinese of eastern China. http://www.jbr-pub.org/ch/reader/view_abstract.aspx?file_no=jbr110503&flag=1 13 Mutational screening of affected cardiac tissues and peripheral blood cells identified novel somatic mutations in GATA4 in patients with ventricular septal defect. J Biomed Res, 2011; 25(6):425-430 Chunyan Chenga, Yuan Lina, Fan Yangb, Wenjing Wangb, Chong Wub, Jingli Qina, Xiuqin Shaoa, Lei Zhoua a Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China; b Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing 100871, China. Abstract: 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 intronexon 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. http://www.jbr-pub.org/ch/reader/view_abstract.aspx?file_no=JBR110607&flag=1 14 uercetin attenuates the progression of monocrotaline-induced pulmonary hypertension in rats. J Biomed Res, 2012; 26(2):98-102 Hanhua Gao, Can Chen, Shi'an Huang, Bo Li Department of Cardiology, the Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, China. Abstract: Pulmonary arterial hypertension (PAH) is a progressive disease associated with increased constriction and remodeling of the pulmonary vasculature. Quercetin is a natural flavonoid and has a variety of pharmacological effects including improvement of endothelial cell function. However, its pharmacological effects on pulmonary hypertension have been rarely reported. We sought to observe the protective effect of quercetin in rats with monocrotaline induced PAH. We divided 30 male Sprague-Dawley rats randomly into three groups with ten rats in each group: the monocrotaline group, the quercetin group and the control group. We found that, com-pared with the controls, the mean pulmonary artery pressure (mPAP) and the right ventricular hypertrophy index in the monocrotaline group were significantly higher (P < 0.01). Quercetin caused a significant reduction both in the mPAP and right ventricular hypertrophy index compared with the monocrotaline group (P < 0.01) while no difference was found between the quercetin group and the control group (P > 0.05). Monocrotaline induced a marked increase in the wall thickness (WT) in small and mid-sized pulmonary arteries compared with the controls (P < 0.01). Monocrotaline also induced a marked increase in the wall area (WA) in small [(56.38±6.65)% in monocrotaline vs. (19.80±4.63)% in control] and mid-sized [(43.71±5.38)% in monocrotaline vs. (14.24±3.66)% in control] pulmonary arteries (P < 0.01). Quercetin treatment markedly reduced monocrotaline induced increase in both WT and WA (P < 0.01), which, however, still remained significantly elevated compared with those of the controls (P < 0.01). Furthermore, compared with controls, proliferating cell nuclear antigen (PCNA) expression in the pulmonary artery tissues was markedly increased by monocrotaline [(45.59±1.27) in monocrotaline vs. (9.64±0.69) in controls], which was significantly attenuated by quercetin. Our animal experiment indicated that quercetin could have protective effects on monocrotaline-induced PAH. http://www.jbr-pub.org/ch/reader/view_abstract.aspx?file_no=JBR120205&flag=1 15 Resveratrol inhibits angiotensin II-induced ERK1/2 activation by downregulating quinone reductase 2 in rat vascular smooth muscle cells. J Biomed Res, 2012; 26(2):103-109 Xiwen Zhanga, Yao Wanga, Weiwei Yangb, Xiaofeng Houa, Jiangang Zoua, Kejiang Caoa a Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China; b Department of Nephrology, Huai'an First People's Hospital affiliated to Nanjing Medical University, Huai'an, China. Abstract: Our previous studies showed that resveratrol could inhibit the proliferation of vascular smooth muscle cells (VSMCs) and repress mRNA and protein expression of quinone reductase 2 (NQO2). This study further explored the potential mechanisms whereby resveratrol inhibits the proliferation of rat VSMCs. Lentiviral vectors that incorporated NQO2 small interfering RNA (siRNA) were constructed and transduced into rat VSMCs. The cell proliferation was detected using the bromodeoxyuridine (BrdU) assay. Cultured rat VSMCs were stimulated with angiotensin II and the level of reactive oxygen species (ROS) was measured using a ROS assay kit. A real-time quantitative PCR was used to detect NQO2 mRNA levels. Extracellular signal-regulated kinase (ERK1/2) and NQO2 protein expression were determined by Western blotting analysis. The inhibitory effect of resveratrol (10 and 50 µmol/L) on the proliferation of rat VSMCs in the NQO2 siRNA group was significantly weaker than that in the normal and scrambled siRNA group (P < 0.01). The ROS level in the NQO2 siRNA and resveratrol (50 µmol/L) treatment groups were lower than that in the normal and scrambled siRNA groups (P < 0.01 in both). Compared with the normal and scrambled siRNA group, the phosphorylation of ERK1/2 was significantly decreased in the NQO2 siRNA and resveratrol (50 µmol/L) treatment group (P < 0.01 in both). In conclusion, high concentration of resveratrol inhibits angiotensin II-induced ERK1/2 phosphorylation and subsequent proliferation by down-regulation of NQO2 in cultured rat VSMCs. http://www.jbr-pub.org/ch/reader/view_abstract.aspx?file_no=JBR120206&flag=1 16 Preliminary feasibility and hemodynamic performance of a newly-developed self-expanding bioprosthesis and 16-F delivery system in transcatheter aortic valve implantation in sheep. J Biomed Res, 2012; 26(3):211-218 Jing Caia, Yanhui Shenga, Shijiang Zhangb, Wei Suna, Rong Yanga, Liping Miaoa, Xiangqing Konga a Department of Cardiology, the First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, China; b Department of Cardiac Surgery, the First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, China. Abstract: We sought to evaluate the feasibility and hemodynamic performance of a new self-expanding bioprosthesis and 16-F delivery system in sheep. A 23-mm new self-expanding aortic bioprosthesis was implanted in sheep (n = 10) with a 16-F catheter via the right common carotid artery. Each sheep underwent angiography and coronary angiography before intervention, immediately and 1 h after stent implantation. Electrocardiographic monitoring was carried out during and 2 h after the procedure. Transthoracic echocardiography was employed to detect hemodynamic performance before intervention, immediately and 1 and 2 h after stent implantation. All sheep were euthanized 2 h after successful implantation for macroscopic inspection. In all cases, the new self-expanding aortic bioprosthesis was successfully delivered to the aortic root and released with a 16-F catheter. Successful implantation was achieved in 8 of 10 sheep. Hemodynamic performance and device position of successful implantation were stable 2 h after device deployment. Atrioventricular block was not observed. We conclude that it is feasible to implant the new self-expanding aortic valve with a 16-F delivery system into sheep hearts via the retrograde route. http://www.jbr-pub.org/ch/reader/view_abstract.aspx?file_no=JBR120309&flag=1 17 Telmisartan prevents high-fat diet-induced hypertension and decreases perirenal fat in rats. J Biomed Res, 2012; 26(3):219-225 Yaping Wang, Yan Song, Meng Suo, Xin Jin, Gang Tian Department of Cardiology, the First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China. Abstract: We sought to investigate the effects of telmisartan on high-fat diet-induced hypertension and to explore the possible underlying mechanisms. Rats receiving high-fat diet were randomly divided into two groups, the telmisartan group (n = 9) and the high-fat diet group (n = 10). The control group consisted of age-matched rats on a regular diet (n = 10). At the end of the treatment, the body weight, blood pressure, insulin sensitivity and serum adiponectin levels of all rats were examined, and their visceral fat was extracted and weighed. Our results showed that telmisartan improved insulin resistance and dyslipidemia and increased serum adiponectin levels. Telmisartan also lowered both systolic blood pressure and diastolic blood pressure, and decreased the accumulation of perirenal fat associated with high-fat diet. Furthermore, telmisartan increased adiponectin mRNA expression in the perirenal fat. Correlation analysis showed that both systolic blood pressure and diastolic blood pressure were positively correlated with perirenal fat. These effects of telmisartan may be mediated through decreases in perirenal fat and contributed to the improvement of perirenal fat function. Our findings suggested a strong link between perirenal fat and high-fat diet-induced hypertension, and identified telmisartan as a potential drug for the treatment of obesity-related hypertension. http://www.jbr-pub.org/ch/reader/view_abstract.aspx?file_no=JBR120310&flag=1 18 Glycine attenuates myocardial ischemia-reperfusion injury by inhibiting myocardial apoptosis in rats. J Biomed Res, 2012; 26(5):346-354 Xiaozheng Zhonga, Xiaoyu Lia, b, Lingling Qiana, Yiming Xub, Yan Lua, Jing Zhangb, Nan Lia, Xudong Zhub, Jingjing Bena, Qing Yanga, Qi Chena, b a Atherosclerosis Research Center, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, Jiangsu 210029, China; b State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, China. Abstract: Glycine is a well-documented cytoprotective agent. However, whether it has a protective effect against myocardial ischemia-reperfusion injury in vivo is still unknown. By using an open-chest anesthetized rat model, we found that glycine reduced the infarct size by 21% in ischemia-reperfusion injury rats compared with that in the vehicle-treated MI/R rats. The left ventricular ejection fraction and fractional shortening were increased by 19.11% and 30.98%, respectively, in glycine-treated rats. The plasma creatine kinase levels in ischemia-reperfusion injury rats decreased following glycine treatment. Importantly, administration of glycine significantly inhibited apoptosis in post-ischemia-reperfusion myocardium, which was accompanied by suppression of phosphorylated p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase, as well as the Fas ligand. These results suggest that glycine attenuates myocardial ischemia-reperfusion injury in vivo by inhibiting cardiomyocytes apoptosis. http://www.jbr-pub.org/ch/reader/view_abstract.aspx?file_no=JBR120506&flag=1 19 left ventricular hypertrophy amplifies the QT, and Tp-e intervals and the Tp-e/ QT ratio of left chest ECG. J Biomed Res, 2010; 24(1):69-72 Zhao Zhao, Zuyi Yuan, Yuqiang Ji, Yue Wu, Yinzhi Qi. Department of Cardiology, Key Laboratory of Environmental Genes Related to Diseases, Ministry of Education, the First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China. Abstract: Objective: To evaluate the changes in Tp-e interval (an interval from the peak to the end of the T wave), QT interval and Tp-e/QT ratio of the body surface ECG in patients with left ventricular hypertrophy (LVH). Methods: The Tp-e interval and QT interval were measured on body surface ECGs in 42 patients without either hypertension or LVH (control group), 41 patients having hypertension but not LVH (non-LVH group), and 38 patients with both hypertension and LVH (LVH group). Results: The mean corrected QT (QTc) interval, and mean corrected Tp-e[T(p-e)c] interval were significantly longer in the LVH group (0.430±0.021s vs. 0.409±0.019s, p < 0.01; 0.098±0.013s vs. 0.088±0.011s, respectively) than those in the control group. The Tp-e/QT ratio was also amplified in LVH group (0.232±0.028 vs.0.218±0.027) (p < 0.05). Conclusion: LVH increased the QT interval, Tp-e interval and Tp-e/QT ratio of the body surface ECG. http://www.jbr-pub.org/ch/reader/view_abstract.aspx?file_no=jbr100110&flag=1 20 An Implanted Closed-loop Chip System for Heart Rate Control: System Design and Effects in Conscious Rats. J Biomed Res, 2010; 24(2):107-114 Yuxuan Zhoua, Yuan Yuana, Juan Gaob, Ling Yanga, Feng Zhangb, Guoqing Zhub, Xingya Gaob a Department of Biomedical Engineering, Nanjing Medical University, Nanjing, Jiangsu 210029, China; b Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China. Abstract: Objective: To evaluate the efficiency of an implanted chip system for the control of heart rate (HR). Methods: The HR was recorded in six conscious Sprague-Dawley (SD) rats. An implanted chip system was designed to regulate the HR by stimulating the right cervical vagus nerve according to the feedback of real time HR. Each rat was subjected to 30-min regulation and 30-min recovery. The change of HR during the regulation period was compared with the control. The ECG was recorded during the experiment for 24 h. Results: The ECG signals were successfully recorded during the experiment. The HR was significantly decreased during the period of regulation compared with control (-79.3 ± 34.5, P < 0.01, n = 6) and then recovered to normal after regulation. Conclusion: The described implanted chip system can regulate the HR to a designated set point. http://www.jbr-pub.org/ch/reader/view_abstract.aspx?file_no=jbr100203&flag=1 21 Apelin and vascular endothelial growth factor are associated with mobilization of endothelial progenitor cells after acute myocardial infarction Jiaxin Yea, Ping Nia, Lina Kangb, Biao Xua a Department of Cardiology, Drum Tower Clinical College Affiliated with Nanjing Medical University, Nanjing, Jiangsu 210008, China; b Department of Cardiology, Drum Tower Hospital (L.N.K.), Nanjing, Jiangsu 210008, China. Abstract: This study was designed to determine the levels of early endothelial progenitor cells (EPCs), apelin, vascular endothelial growth factor (VEGF) and stromal cell-derived growth factor-1 (SDF-1) after acute myocardial infarction (AMI), and to investigate the relationships between these cytokines and early EPCs. Early EPCs, defined as CD133+, KDR+, and CD34+ cells, were quantified by flow cytometry. The levels of early EPCs and those cytokines in AMI patients were significantly different from those with coronary artery disease or controls (P < 0.05). Plasma apelin levels were inversely correlated with Gensini score and early EPCs (both P < 0.01). Early EPCs, VEGF and SDF-1 showed different patterns of changes in AMI patients during the first 24 h. The trend in the change of early EPCs was proportionally correlated with that of VEGF (P < 0.05). AMI patients exhibited increased early EPCs with remarkably decreased apelin levels and enhanced VEGF levels. http://www.jbr-pub.org/ch/reader/view_abstract.aspx?flag=1&file_no=JBR120602 22 Genetic variants of the class A scavenger receptor gene are associated with coronary artery disease in Chinese Min Zhanga,#, Yan Zhangb, Shuaishuai Zhua, Xiaoyu Lia, Qing Yanga, Hui Baia, Qi Chena,* a Atherosclerosis Research Center, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Institute of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, China; b Department of Medicine, China-Japan Friendship Hospital, Beijing 100029, China. Abstract: The class A scavenger receptor, encoded by the macrophage scavenger receptor 1 (MSR1) gene, is a pattern recognition receptor (PPR) primarily expressed in macrophages. It has been reported that genetic polymorphisms of MSR1 are significantly associated with the number of diseased vessels and coronary artery narrowing greater than 20% in Caucasians. However, whether it links genetically to coronary artery disease (CAD) in Chinese is not defined. Here, we performed an independent case-control study in a Chinese population consisting of 402 CAD cases and 400 controls by genotyping ten single nucleotide polymorphisms (SNPs) of MSR1. We found that rs416748 and rs13306541 were significantly associated with an increased risk of CAD with per allele odds ratio (OR) of 1.56 [95% confidence interval (CI) = 1.28-1.90; P < 0.001] and 1.70 (95% CI = 1.27-2.27; P < 0.001), respectively. Our results indicate that genetic variants of MSR1 may serve as predictive markers for the risk of CAD in combination with traditional risk factors of CAD in Chinese population. http://www.jbr-pub.org/ch/reader/view_abstract.aspx?flag=1&file_no=JBR120604 23 Enhanced sympathetic activity and cardiac sympathetic afferent reflex in rats with heart failure induced by adriamycin Shujuan Zhang, Feng Zhang, Haijian Sun, Yebo Zhou, Ying Han* Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China Abstract: Our previous studies have shown that the cardiac sympathetic afferent reflex is enhanced in rats with chronic heart failure (CHF) induced by coronary artery ligation and contributes to the over-excitation of sympathetic activity. We sought to determine whether sympathetic activity and cardiac sympathetic afferent reflex were enhanced in adriamycin-induced CHF and whether angiotensin II (Ang II) in the paraventricular nucleus (PVN) was involved in enhancing sympathetic activity and cardiac sympathetic afferent reflex. Heart failure was induced by intraperitoneal injection of adriamycin for six times during 2 weeks (15 mg/kg). Six weeks after the first injection, the rats underwent anesthesia with urethane and α-chloralose. After vagotomy and baroreceptor denervation, cardiac sympathetic afferent reflex was evaluated by renal sympathetic nerve activity and mean arterial pressure (MAP) response to epicardial application of capsaicin (1.0 nmol). The response of MAP to ganglionic blockade with hexamethonium in conscious rats was performed to evaluate sympathetic activity. The renal sympathetic nerve activity and cardiac sympathetic afferent reflex were enhanced in adriamycin rats and the maximum depressor response of MAP induced by hexamethonium was significantly greater in adriamycin rats than that in control rats. Bilateral PVN microinjection of angiotensin II (Ang II) caused larger responses of the cardiac sympathetic afferent reflex, baseline renal sympathetic nerve activity and MAP in adriamycin rats than control rats. These results indicated that both sympathetic activity and cardiac sympathetic afferent reflex were enhanced and Ang II in the PVN was involved in the enhanced sympathetic activity and cardiac sympathetic afferent reflex in rats with adriamycin-induced heart failure. http://www.jbr-pub.org/ch/reader/view_abstract.aspx?flag=1&file_no=JBR120605 24 Overexpression of angiopoietin-1 reduces doxorubicin-induced apoptosis in cardiomyocytes Danyang Rena, Quan Zhub, Jiantao Lia, Tuanzhu Hac, Xiaohui Wangc, Yuehua Lia,* a Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China; b Department of Thoracic & Cardiovascular Surgery, the First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, China; c Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA. Abstract: Doxorubicin (Dox) is a major anticancer chemotherapeutic agent. However, it causes cardiomyopathy due to the side effect of cardiomyocyte apoptosis. We have previously reported that angiopoietin-1 significantly reduced myocardial infarction after ischemic injury and protected cardiomyocytes from oxidative stress-induced apoptosis. It is hypothesized that angiopoietin-1 may protect cardiomyocytes from Dox-induced apoptosis. Cardiomyocytes H9C2 were transfected with adenovirus expressing angiopoietin-1 (Ad5-Ang-1) 24 h before the cells were challenged with Dox at a concentration of 2 µmol/L. Ad5-GFP served as the vector control. Cardiomyocyte apoptosis was evaluated using Annexin V-FITC staining and caspase-3 and caspase-8 activity was determined by Western blotting. The results showed that Dox treatment significantly induced cardiomyocyte apoptosis as evidenced by the greater number of Annexin V-FITC stained cells and increases in caspase-3 and caspase-8 activity. In contrast, overexpression of angiopoietin-1 significantly prevented Dox-induced cardiomyocyte apoptosis. To elucidate the mechanisms by which angiopoietin-1 protected cells from Dox-induced apoptosis, we analyzed both extrinsic and intrinsic apoptotic signaling pathways. We observed that angiopoietin-1 prevented Dox-induced activation of both extrinsic and intrinsic apoptotic signaling pathways. Specifically, angiopoietin-1 prevented DOX-induced increases in FasL and Bax levels and cleaved caspase-3 and caspase-8 levels in H9C2 cells. In addition, overexpression of angiopoietin-1 also activated the pro-survival phosphoinositide-3 kinase (PI3K)/Akt signaling pathway and decreased Dox-induced nuclear factor-kappaB (NF-κB) activation. Our data suggest that promoting the expression of angiopoietin-1 could be a potential approach for reducing Dox-induced cardiomyocyte cytoxicity. http://www.jbr-pub.org/ch/reader/view_abstract.aspx?flag=1&file_no=JBR120606 Cardiovascular Surgery 25 Clinical results of tricuspid valve replacement — a 21-case report. J Biomed Res, 2010; 24(1):73-76 Yu Zhuanga, Jie Zhoub, Mingdi Xiaoa, Zhongxiang Yuana, Chengbao Lua, Min Yua, Lei Lina a Department of Cardiovascular Surgery, Shanghai Jiao Tong University Affiliated First People's Hospital, Shanghai 200080, China; b Department of English, College of Foreign Language, Guangxi University for Nationalities, Nanning, Guangxi 530006, China. Abstract: Objective: To summarize the clinical experiences of 21 patients treated with tricuspid valve replacement (TVR) and investigate the surgical indications and methods. Methods: Data from 21 patients who underwent TVR from December 2002 to March 2009 were retrospectively collected and analyzed. The mean age was 48.86±15.37 years (range: 20-72 years). The underlying disease of the patients was classified as rheumatic (n = 10), congenital (n = 8), endocarditis (n = 2) or chest trauma (n = 1). Previous cardiac surgery had been performed in 12 patients (57.14%). Results: In-hospital death occurred in two patients (9.52%). Postoperative morbidities included cardiac failure (n = 2), bleeding related re-operation (n = 1), and plural effusion (n = 2). Conclusion: The early outcomes of TVR were acceptable. At the present time TVR can be performed through optimal perioperative management. http://www.jbr-pub.org/ch/reader/view_abstract.aspx?file_no=jbr100111&flag=1 26 Coronary artery bypass grafting with concomitant resection for carcinoma of lung. J Biomed Res, 2010; 24(1):77-80 Yangyang Zhang, Yanhu Wu, Biao Yuan, Xiang Liu, Sheng Zhao, Zhi Li, Yu Xia. Department of Cardiothoracic Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China. Abstract: A 69-year-old woman with angina had a lesion in the left lower lobe on chest film. Angiography revealed coronary artery disease in three vessels. Combined off pump coronary artery bypass grafting (CABG) and left lower lobectomy were performed through median sternotomy. This approach avoids complications due to staged operations and cardiopulmonary bypass (CPB). This report shows that simultaneous off pump CABG and pulmonary operations can be performed safely in patients with coronary artery disease (CAD) associated with lung cancer. http://www.jbr-pub.org/ch/reader/view_abstract.aspx?file_no=jbr100112&flag=1 27 Surgical repair of thoracoabdominal aortic aneurysms using the critical artery reattachment technique. J Biomed Res, 2011; 25(3):220-223 Yulong Houa, Jianqiang Zhaoa, Wei Guoa, Su Huanga, Chunling Wangb a Department of Cardiothoracic Surgery, and bDepartment of Hematology, Huai’an First Hospital Affiliated with Nanjing Medical University, Huai’an, Jiangsu 223300, China. Abstract: In the study, we sought to retrospectively analyze the effectiveness and safety of surgical repair of thoracoabdominal aortic aneurysm using the critical artery reattachment technique. Twenty-three consecutive thoracoabdominal aortic aneurysm patients were treated using the technique of sequential aortic clamping and critical artery reattachment. The entire procedure was technically successful in all patients. One died of renal failure and the overall hospital mortality was 4.35%. The total incidence of complications was 21.74%. At a median follow-up of 33 months, all patients were alive. We found that the application of critical artery reattachment technique in the management of thoracoabdominal aortic aneurysm provides excellent short- and mid-term results in most patients. It could markedly increase the curing rate and reduce the morbidity of postoperative complications including paraplegia, ischemia of abdominal viscera, and renal failure. http://www.jbr-pub.org/ch/reader/view_abstract.aspx?file_no=jbr110310&flag=1 28 Familial cardiac myxoma with multifocal recurrences: a case report and review of the literature. J Biomed Res, 2011; 25(5):368-372 Hailong Caoa, Yanhu Wub, Jinfu Zhub, Yijiang Chenb a Department of Thoracic and Cardiovascular Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, China; b Department of Thoracic and Cardiovascular Surgery, the First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu 210029, China. Abstract: We report a case of myxoma with multiple recurrences in both the atrium and ventricle in a 26-year-old woman five years after the surgical removal of left atrial myxoma. Her 52-year-old mother had a similar medical history. To our knowledge, this was the first familial case who suffered multifocal cardiac myxoma recurrences without any sign of the myxoma complex. Based on our understanding of the mechanism of recurrence, the approaches to prevent the recurrence, and markers to predict recurrence, we propose that multifocal recurrences, as reported herein, may result from a combination of familial predisposition and multifocal onset. The biatrial surgical approach and transesophageal echocardiography are preferred for patients with recurrent cardiac myxomas, especially for those with multiple recurrences and familial myxoma. Immunological and genetic screenings may help to identify family members at risk for developing this disease. http://www.jbr-pub.org/ch/reader/view_abstract.aspx?file_no=jbr110509&flag=1