Intramyocardial Injection of Stem Cells in Pig Myocardial Infarction Model: The First Trial in Korea

Although cell therapy is emerged for cardiac repair, its efficacy is modest by intracoronary infusion. Therefore, we established the intramyocardial delivery technique using a left ventricular (LV) mapping system (NOGA® XP) using 18 pigs. After adipose tissue-derived mesenchymal stem cells (ATSCs) were delivered intramyocardially to porcine infarcted heart, LV ejection fraction (EF) was increased, and LV chamber size was decreased. We proved the therapeutic effect of intramyocardial injection of ATSC through a LV mapping system in the porcine model for the first time in Korea. The adoption of this technique may accelerate the translation into a clinical application in the near future.

Cognitive Impairments in Clinically Stable Late-Life Depression : Relationship to Cardiovascular Risk : A Pilot Study

OBJECTIVE: The purpose of this study was to test the hypothesis that cardiovascular risk is associated with cognitive impairments in clinically stable late-life depression. METHODS: A total of 59 clinically stable late-life depression patients over age 60 were enrolled in a cross-sectional study. Evaluation tools used in this study include Hamilton Rating Scale for Depression, Geriatric Depression Scale, State-Trait Anxiety Inventory, the Framingham general cardiovascular disease risk profile and the cognitive function battery designed for this study. Correlation analysis, analysis of variance and analysis of covariance were performed. RESULTS: Patients with higher cardiovascular risk performed significantly poorer in the domains of executive function and short-term or long-term memory. In models adjusted for age, sex, education, 10% higher cardiovascular risk was associated with poorer executive function. CONCLUSION: Our findings suggested that cardiovascular risk could be a significant factor associated with poor executive function in clinically stable late-life depression and the management which is necessary as a component of treatment planning. This pilot study provided good prospects for future studies to document this relationship on larger samples.

The Relationship among Psychopathology, Cognitive Function, Insight and Quality of Life in Elderly Patients with Chronic Schizophrenia

OBJECTIVE: The aim of this study was to investigate the association with psychopathology, cognitive function, insight and quality of life (QOL) in elderly patients with chronic schizophrenia over age 55. METHODS: 103 schizophrenic patients over age 55 with illness duration over 10 years, are enrolled in a cross-sectional study. The subjects were assessed by the Korean version of 4th Revision of Schizophrenia Quality of Life Scale, Korean Version of Scales to Assessment Unawareness of Mental Disorder, Positive and Negative Syndrome Scale (PANSS) and the cognitive function battery designed for this study. Multiple regression stepwise selection models were executed to identify the relations among variables, and the contributing factors to QOL. RESULTS: Among schizophrenic patients with lower illness-severity with PANSS total score below 75, higher PANSS positive subscale score and lower number of hospitalization were related to lower QOL. Among patients with higher illness-severity with PANSS total score of 75 and over, higher PANSS general psychopathology subscale score, better intelligence, better delayed recall function, worse attention, better awareness of medication effect and later onset were related to lower QOL. CONCLUSION: Results of our study suggest that improvement in positive symptom and general psychopathology could increase the QOL in elderly patients with chronic schizophrenia over age 55. And the management which could improve attention, awareness of need for medication would attribute the QOL.

Angiopoietin-Like 4 Is Involved in the Poor Angiogenic Potential of High Glucose-Insulted Bone Marrow Stem Cells

BACKGROUND AND OBJECTIVES: Diabetes is reported to reduce the function or number of progenitor cells. We compared the gene expression patterns of bone marrow-derived mesenchymal stem cells from diabetic (DM-BMCs) and healthy (non-DM-BMCs) rats and suggested Angiopoietin-like 4 (Angptl4) could be a responsible factor for impaired angiogenesis of DM-BMCs. SUBJECTS AND METHODS: BMCs were isolated from DM or non-DM rat, and in vitro angiogenesis activity was compared by tube formation assay on Matrigel and complementary deoxyribonucleic acid expression was analyzed by microarray with or without oxytocin treatment. Human BMCs (hBMCs) were treated with high glucose, and were performed polymerase chain reaction, Western blot, and enzyme-linked immunosorbent assay. Angptl4 plasmid DNA and micro ribonucleic acid-132 (miR-132) were transfected to immortalized hBMCs. RESULTS: In vitro angiogenesis assay showed the impaired tube formation in DM-BMCs, and slightly recovery by oxytocin treatment. Angptl4, an adipokine, was upregulated in DM-BMCs compared to non-DM-BMCs. Oxytocin treatment reduced Angptl4 in DM-BMCs. In hBMCs, overexpression of Angptl4 attenuated the tube formation. In addition to Angptl4, miR-132 was increased by high glucose treatment. Collectively, high glucose resulted in impaired tube formation through miR-132 induction and Angptl4 upregulation in BMCs. CONCLUSION: Our results show that the angiogenic activity of BMCs is impaired by high glucose stress, which would be mediated by Angptl4 and miR-132.

Therapeutic Potential of Umbilical Cord Blood-Derived Mesenchymal Stem Cells in Ischemic Myocardium

BACKGROUND AND OBJECTIVES: We designed this study to determine the therapeutic potentials of umbilical cord blood (UCB)-mesenchymal stem cells (MSCs), as compared with bone marrow (BM)-MSCs. MATERIALS AND METHODS: MSCs were isolated from UCB and BM. For the in vivo study, myocardial infarction was induced by ligation of the left anterior descending coronary artery (LAD) in rats for 30 min, and this was followed by release; the MSCs were then injected into a designated point around the infarcted area. Echocardiographs were performed two weeks after surgery. For the in vitro study, a cDNA microarray and cytokine array were performed to compare the MSCs from UCB and from BM. Cell migration was assessed by a wound scratch assay, and the level of cardiac ankyrin repeat protein (CARP) was determined by reverse transcriptase-polymer chain reaction (RT-PCR) or Western blot analysis. RESULTS: For the echocardiograph findings, the fractional shortening (FS) was 43.9% in the UCB-MSCs group and it was 38.6% in the BM-MSC group. The ejection fraction (EF) was 79.8% in the UCB-MSC group and it was 72.4% in the BM-MSC group (control FS: 26.2% and the control EF: 56.6%). CARP was one of the highly expressed genes in the UCB-MSCs on the cDNA microarray. The mRNA and the expressed level of CARP protein in the UCB-MSCs were higher than those in the BM-MSCs. The cell migration of the CARP small interfering ribonucleic acid (siRNA) transfected UCB-MSCs was delayed compared to that of the normal UCB-MSCs (p<0.05) CONCLUSION: Our study directly compared the two types of MSCs from UCB and BM, and we suggest that the CARP molecule might be responsible for the motility of UCB-MSCs.

The Protective Effect of Curcumin on Myocardial Ischemia-Reperfusion Injury

BACKGROUND AND OBJECTIVES: Myocardial ischemia-reperfusion (I/R) injury is one of the major causes of cardiac mortality. Curcumin, an active component extracted from turmeric in curry, inhibits inflammatory responses. This study was designed to investigate whether curcumin can exert beneficial effects on myocardial I/R injury. MATERIALS AND METHODS: Sprague-Dawley male rats received a normal diet or a curcumin diet (80 mg/kg/d) for one week, and I/R injury was induced by ligating the left anterior descending artery (LAD) for 30 min followed by release. After 24 hours, the myocardium was extracted to evaluate the myeloperoxidase (MPO) activity and the vascular cellular adhesion molecule (VCAM)-1 protein level. The apoptotic cardiomyocytes and neutrophils were counted and quantified by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining at 14 days after I/R. RESULTS: In the infarcted myocardium of the curcumin-fed rats, the MPO activity (32.9+/-2.2% of the control, p=0.001) and the VCAM-1 protein (28.7+/-2.9% of control, p=0.001) level were significantly attenuated. The number of neutrophils was lower in the curcumin-fed rats (57+/-12% of the control, p=0.024). A reduction of the apoptotic cardiomyocytes was also observed in the curcumin-fed I/R rats (36+/-9.2% of the control, p=0.032). CONCLUSION: The cardioprotective effects of curcumin on an I/R injury rat model could include anti-inflammation activities and inhibition of apoptosis that occurred in the cardiomyocytes. Our findings suggest that curcumin has a positive contribution as a dietary supplement for the prevention of heart disease.

Curcumin Attenuates Nuclear Factor-kappaB, c-Jun N-Terminal Kinase and p38 in Tumor Necrosis Factor-alpha-Stimulated Endothelial Cells

BACKGROUND AND OBJECTIVES: Curcumin, a yellow pigment of turmeric in curry, has been reported to interfere with nuclear factor (NF)-kappaB. This study was designed to investigate the underlying pathway of the anti-inflammation effect of curcumin on endothelial cells. MATERIALS AND METHODS: Human umbilical vein endothelial cells (HUVECs) were stimulated with tumor necrosis factor (TNF)-alpha (10 ng/mL). The levels of intracellular reactive oxygen species (ROS) were examined using a fluorescent dye DCFH-DA, and the adhesion of U-937 monocytes to the HUVECs was then examined. Nuclear factor kappa B (NF-kappaB) activation was determined by the NF-kappaB p65 translocation to the nucleus via immunocytochemistry. The expression of the NF-kappaB dependent pro-inflammatory molecules were measured by RT-PCR and ELISA. The phosphorylations of c-Jun N-terminal protein kinase (JNK), p38 and STAT-3 (signal transducer and activator of transcription-3) were measured by Western blotting. RESULTS: Curcumin blocked the activation of NF-kappaB by TNF-alpha, and it also reduced the ROS, monocyte adhesion and the phosphorylation of JNK, p38 and STAT-3 in the TNF-alpha-stimulated HUVECs. The expression of intracellular cell adhesion molecule (ICAM)-1, monocyte chemoattractant protein (MCP)-1, and interleukin (IL)-8 were attenuated by curcumin at both the transcription and translation levels. CONCLUSION: We suggest that curcumin could contribute to protection against the adverse vascular effects of the pro-inflammatory response through the modulation of NF-kappaB, JNK, p38 and STAT-3, and this is in addition to its antioxidant effect in endothelial cells.

Carvedilol Inhibits Expressions of Vascular Cell Adhesion Molecule-1, Intercellular Adhesion Molecule-1, Monocyte Chemoattractant-1, and Interleukin-8 via NF-kappaB Inhibition in Human Endothelial Cells

BACKGROUND AND OBJECTIVES: Carvedilol is an anti-oxidative, the cardioprotective effects of which are mediated by the inhibition of NF-kappaB activation. The present study was designed to examine the effects of carvedilol, an alpha1- and beta-blocker, on tumor necrosis factor (TNF)-alpha stimulated human umbilical vein endothelial cells (HUVEC). Materials and METHODS: HUVEC were treated with TNF-alpha (10 ng/mL) in either the absence or presence of carvedilol. The levels of intracellular reactive oxygen species (ROS) were examined using a fluorescent dye DCFH-DA, with the adhesion of U-937 monocyte to the HUVEC. Nuclear factor kappa B (NF-kappaB) activation was determined by NF-kappaB p65 translocation to the nucleus using Western blotting and immunocytochemistry. The expressions of NF-kappaB dependent pro-inflammatory molecules, i.e., vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-8, were measured by RT-PCR and ELISA. Bcl-2 and phosphorylation of c-Jun N-terminal protein kinase (JNK) were measured using Western blotting. RESULTS: TNF-alpha treatment increased the activation of NF-kappaB, suppressed Bcl-2, and increased the phosphorylation of JNK, the ROS level and the adhesion of U-937. The levels of mRNA and protein expressions of VCAM-1, ICAM-1, MCP-1 and IL-8 were up-regulated by TNF-alpha. Carvedilol inhibited the phosphorylation of JNK, ROS formation and the adhesion of U-937 monocyte. In addition, carvedilol reduced the production of VCAM-1, ICAM-1, MCP-1 and IL-8 at the mRNA and protein levels, via the suppression of NF-kappaB activation. CONCLUSION: These results suggested that the anti-inflammatory effects of carvedilol on TNF-alpha stimulated endothelial cells could be explained by its ROS-scavenging and NF-kappaB inactivation properties.