Early Growth Response Factor-1 Is Associated With Intraluminal Thrombus Formation in Human Abdominal Aortic Aneurysm

ObjectivesThe goal of this study was to investigate the expression of early growth response-1 (Egr-1), a vascular pathogenic transcription factor, and its potential relationship with tissue factor (TF), a key player during the thrombus formation in the abdominal aortic aneurysm (AAA) wall.BackgroundAlthough intraluminal thrombus is a common finding in human AAA, the molecular mechanism of the thrombus formation has not been studied.MethodsDuring the elective AAA repair, specimens were taken from the thrombus-covered and thrombus-free portions of the aneurysmal wall in each of 16 patients with AAA and analyzed to assess the differential expression of Egr-1 and TF. The proinflammatory and prothrombogenic activities of Egr-1 in vasculature were evaluated in vitro and in vivo by overexpressing it using adenovirus.ResultsThe expression of both Egr-1 and TF was significantly increased in the thrombus-covered wall compared with the thrombus-free wall, in which their up-regulation in the thrombus-covered wall was strongly correlated with each other (p < 0.005, r = 0.717). Adenoviral overexpression of Egr-1 in human vascular smooth muscle and endothelial cells was found to up-regulate the expression of TF and inflammation-related genes. Moreover, Egr-1 overexpression in endothelial cells increased their adhesiveness to monocytes and also substantially promoted the intravascular thrombus formation in vivo, as shown in the inferior vena cava ligation experiment of the rat.ConclusionsThe present study demonstrates the differential up-regulation of Egr-1 in the thrombus-covered wall of human AAA and also suggests its possible contribution to the thrombogenic and inflammatory pathogenesis in human AAA

Vascular differentiation of multipotent spermatogonial stem cells derived from neonatal mouse testis

We previously reported the successful establishment of embryonic stem cell (ESC)-like multipotent spermatogonial stem cells (mSSCs) from neonatal mouse testis. Here, we examined the ability of mSSCs to differentiate into vascular endothelial cells and smooth muscle cells, and compared to that of mouse ESCs. We used real-time reverse transcriptase polymerase chain reaction and immunohistochemistry to examine gene expression profiles of mSSCs and ESCs during in vitro vascular differentiation. Both mSSCs and ESCs exhibited substantial increase in the expression of mesodermal markers, such as Brachyury, Flk1, Mesp1, Nkx2.5, and Islet1, and a decrease in the expression of pluripotency markers, such as Oct3/4 and Nanog during the early stage of differentiation. The mRNA levels of vascular endothelial (VE)-cadherin and CD31 gradually increased in both differentiated mSSCs and ESCs. VE-cadherin- or CD31-positive cells formed sprouting branch-like structures, as observed during embryonic vascular development. At the same time, vascular smooth muscle cell-specific markers, such as myocardin and α-smooth muscle actin (SMA), were also highly expressed in differentiated mSSCs and ESCs. Immunocytochemical analysis revealed that the differentiated cells expressed both α-SMA and SM22-α proteins, and exhibited the intracellular fibril structure typical of smooth muscle cells. Overall, our findings showed that mSSCs have similar vascular differentiation abilities to those of ESCs, suggesting that mSSCs may be an alternative source of autologous pluripotent stem cells for vascular regeneration

Functional Recapitulation of Smooth Muscle Cells Via Induced Pluripotent Stem Cells From Human Aortic Smooth Muscle Cells

Rationale: Generation of induced pluripotent stem (iPS) cells has been intensively studied by a variety of reprogramming methods, but the molecular and functional properties of the cells differentiated from iPS cells have not been well characterized. Objective: To address this issue, we generated iPS cells from human aortic vascular smooth muscle cells (HASMCs) using lentiviral transduction of defined transcription factors and differentiated these iPS cells back into smooth muscle cells (SMCs). Methods and Results: Established iPS cells were shown to possess properties equivalent to human embryonic stem cells, in terms of the cell surface markers, global mRNA and microRNA expression patterns, epigenetic status of OCT4, REX1, and NANOG promoters, and in vitro/in vivo pluripotency. The cells were differentiated into SMCs to enable a direct, comparative analysis with HASMCs, from which the iPS cells originated. We observed that iPS cell-derived SMCs were very similar to parental HASMCs in gene expression patterns, epigenetic modifications of pluripotency-related genes, and in vitro functional properties. However, the iPS cells still expressed a significant amount of lentiviral transgenes (OCT4 and LIN28) because of partial gene silencing. Conclusions: Our study reports, for the first time, the generation of iPS cells from HASMCs and their differentiation into SMCs. Moreover, a parallel comparative analysis of human iPS cell-derived SMCs and parental HASMCs revealed that iPS-derived cells possessed representative molecular and in vitro functional characteristics of parental HASMCs, suggesting that iPS cells hold great promise as an autologous cell source for patient-specific cell therapy. (Circ Res. 2010;106:120-128.)Yu JY, 2007, SCIENCE, V318, P1917, DOI 10.1126/science.1151526Hanna J, 2007, SCIENCE, V318, P1920, DOI 10.1126/science.1152092Takahashi K, 2007, CELL, V131, P861, DOI 10.1016/j.cell.2007.11.019Byrne JA, 2007, NATURE, V450, P497, DOI 10.1038/nature06357Lee TH, 2007, PLOS MED, V4, P1101, DOI 10.1371/journal.pmed.0040186Matsumura H, 2007, NAT METHODS, V4, P23, DOI 10.1038/NMETH973Aoi T, 2008, SCIENCE, V321, P699, DOI 10.1126/science.1154884Dimos JT, 2008, SCIENCE, V321, P1218, DOI 10.1126/science.1158799Barroso-delJesus A, 2008, MOL CELL BIOL, V28, P6609, DOI 10.1128/MCB.00398-08Aasen T, 2008, NAT BIOTECHNOL, V26, P1276, DOI 10.1038/nbt.1503Stadtfeld M, 2008, SCIENCE, V322, P945, DOI 10.1126/science.1162494Okita K, 2008, SCIENCE, V322, P949, DOI 10.1126/science.1164270Tateishi K, 2008, J BIOL CHEM, V283, P31601, DOI 10.1074/jbc.M806597200Zhang JH, 2009, CIRC RES, V104, pE30, DOI 10.1161/CIRCRESAHA.108.192237Soldner F, 2009, CELL, V136, P964, DOI 10.1016/j.cell.2009.02.013Chang SA, 2008, STEM CELLS, V26, P1901, DOI 10.1634/stemcells.2007-0708Park IH, 2008, NATURE, V451, P141, DOI 10.1038/nature06534Lowry WE, 2008, P NATL ACAD SCI USA, V105, P2883, DOI 10.1073/pnas.0711983105Laurent LC, 2008, STEM CELLS, V26, P1506, DOI 10.1634/stemcells.2007-1081Kim JB, 2008, NATURE, V454, P646, DOI 10.1038/nature07061Ross JJ, 2006, J CLIN INVEST, V116, P3139, DOI 10.1172/JCI28184Takahashi K, 2006, CELL, V126, P663Yu JY, 2006, STEM CELLS, V24, P168, DOI 10.1634/stemcells.2005-0292Cowan CA, 2005, SCIENCE, V309, P1369, DOI 10.1126/science.1116447Adhikary S, 2005, NAT REV MOL CELL BIO, V6, P635, DOI 10.1038/nrm1703DALLAFAVERA R, 1982, P NATL ACAD SCI-BIOL, V79, P78241

Aldosterone Upregulates Connective Tissue Growth Factor Gene Expression via p38 MAPK Pathway and Mineralocorticoid Receptor in Ventricular Myocytes

The effect of aldosterone on connective tissue growth factor (CTGF) was examined in rat embryonic ventricular myocytes. Upon aldosterone treatment, CTGF expression was significantly increased in a dose and time-dependent manner. To explore the molecular mechanism for this upregulation, we examined the role of mineralocorticoid receptor. Pre-treatment of an antagonist (spironolactone) at 5-fold excess of aldosterone blocked the CTGF induction by aldosterone, suggesting that the upregulation was mediated by mineralocorticoid receptor. Aldosterone treatment resulted in activation of ERK1/2, p38 MAPK, and JNK pathways with a more transient pattern in p38 MAPK. Blocking studies using pre-treatment of the inhibitor of each pathway revealed that p38 MAPK cascade may be important for aldosterone-mediated CTGF upregulation as evidenced by the blocking of CTGF induction by SB203580 (p38 MAPK inhibitor), but not by PD098059 (ERK1/2 inhibitor) and JNK inhibitor I. Interestingly, JNK inhibitor I and PD098059 decreased the basal level of CTGF expression. On the other hand, pre-treatment of spironolactone abrogated the p38 MAPK activation, indicating that mineralocorticoid receptor mechanism is linked to p38 MAPK pathway. Taken together, our findings suggest that aldosterone induces CTGF expression via both p38 MAPK cascade and mineralocorticoid receptor and that cross-talk exists between the two pathways

Suboptimal Disturbance Observer Design Using All Stabilizing Q Filter for Precise Tracking Control

For several decades, disturbance observers (DOs) have been widely utilized to enhance tracking performance by reducing external disturbances in different industrial applications. However, although a DO is a verified control structure, a conventional DO does not guarantee stability. This paper proposes a stability-guaranteed design method, while maintaining the DO structure. The proposed design method uses a linear matrix inequality (LMI)-based H&infin; control because the LMI-based control guarantees the stability of closed loop systems. However, applying the DO design to the LMI framework is not trivial because there are two control targets, whereas the standard LMI stabilizes a single control target. In this study, the problem is first resolved by building a single fictitious model because the two models are serial and can be considered as a single model from the Q-filter point of view. Using the proposed design framework, all-stabilizing Q filters are calculated. In addition, for the stability and robustness of the DO, two metrics are proposed to quantify the stability and robustness and combined into a single unified index to satisfy both metrics. Based on an application example, it is verified that the proposed method is effective, with a performance improvement of 10.8%

Optimal Disturbance Observer Design for High Tracking Performance in Motion Control Systems

In this paper, a stability-driven optimal disturbance observer (DO) is proposed. The proposed method does not require any plant inverse dynamics to detect introduced disturbances or a stabilizing Q filter. It does not require additional compensators to resolve causality problems, due to the relative degree, or filters to solve instability problems of non-minimum phase plants. Using this method enables wideband and narrowband disturbances to be attenuated by simply multiplying the corresponding peak filters by the baseline weight function. Furthermore, the proposed DO guarantees the stability of closed-loop systems because the already designed outer-loop systems are considered as a target plant to be stabilized and because of the Lyapunov stability-based H&infin; control. In the application example, it was confirmed that the proposed method is effective, and the position error signals were improved by 20.9% in commercial hard disk drives and 36.6% in optical image stabilization systems

Position Control Based on Add-on-Type Iterative Learning Control with Nonlinear Controller for Permanent-Magnet Stepper Motors

In this paper, a current-error-based iterative learning controller (ILC) with a nonlinear controller is proposed to improve the position-tracking performance in permanent-magnet (PM) stepper motors. Our proposed method comprises a current-error-based ILC for mechanical dynamics and a nonlinear controller for current dynamics. A nonlinear controller using a variable structure is designed to obtain the field-oriented control. This nonlinear controller can cause the PM stepper motor become a single-input single-output linear system after finite time. The add-on-type ILC with proportional&ndash;integral control is designed to improve the position-tracking performance as the systems repeatedly perform the same operation. To increase the rate of error convergence, the current-error-based ILC is designed using the plant inversion method. The condition that the error converges to zero is mathematically derived. Thus, the proposed method can reduce the position-tracking error as the systems repeatedly perform the same operation. Furthermore, the proposed method can be easily plugged into the pre-designed controller. The performance of our proposed method was evaluated via simulations. In simulations, it is observed that the proposed method reduces the position-tracking error compared to the previous methods

Impact of frailty severity and severe pain on cognitive function for community-dwelling older adults with arthritis: a cross-sectional study in Korea

Abstract Pain is a major symptom of arthritis in older adults, often leading to frailty and cognitive decline. However, few studies have investigated the relationship among pain, frailty, and cognitive function in older adults with arthritis. This study aimed to investigate the factors influencing cognitive function and the impact of frailty severity and pain on cognitive function in older adults with arthritis using a Korean population-based dataset. This cross-sectional descriptive study involved the secondary data of 1089 participants from the seventh and eighth waves of the Korean Longitudinal Study on Aging. We examined general characteristics, health behaviors, health conditions (including severe pain and frailty), and cognitive function. Participants were categorized based on the presence or absence of pain severity and frailty status as follows: robust, only severe pain, only prefrail, prefrail with severe pain, only frail, and frail with severe pain. Multiple linear regression analysis was performed to establish correlations between groups and cognitive function. The only-prefrail group was the largest (19.7%) among participants experiencing either pain or frailty. Advanced age, sex, level of education, and visual and hearing impairments were significantly associated with cognitive function. Compared to the robust group, only prefrail (β = -1.54, confidence interval [CI] = − 2.33; − 0.76), prefrail with severe pain (β = − 2.69, CI = − 3.52; − 1.87), only frail (β = − 4.02, CI = − 5.08; − 2.97), and frail with severe pain (β = − 5.03, CI = − 5.99; − 4.08) groups were associated with lower Mini-Mental State Examination scores. The study confirmed that severe pain alone does not significantly impact cognitive function in older adults with arthritis. To prevent cognitive decline in this group, assessment of both pain and frailty severity is essential to predict high-risk groups and provide appropriate interventions, such as transfer to hospitals or primary clinics according to the severity of pain and frailty