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ABSTRACT: Increasing evidence has shown that inflammation is involved in pressure overload-induced cardiac remodeling. Monocyte chemoattractant protein-1 (MCP-1) plays a pivotal role in the inflammatory process. However, the mechanisms underlying the upregulation of MCP-1 expression remain poorly understood. In the present study, we examined the hypothesis that an increased production of reactive oxygen species (ROS) mediates the upregulation of MCP-1. In a pressure-overloaded rat heart model with abdominal aortic coarctation (AC), superoxide dismutase-inhibitable cytochrome C reduction assay showed that ROS generation in the myocardium increased significantly at 1 week by 61% (n=8, P<0.01), peaked at 2 weeks and maintained these high levels for 4 weeks. The elevation of ROS was paralleled by the increased expression of MCP-1 and left ventricular remodeling (cardiac hypertrophy, perivascular and interstitial fibrosis). The oral administration of the antioxidant, N-acetylcysteine (NAC, 0.2 g/kg/day), for 2 or 4 weeks, significantly attenuated ROS production by 69 and 68%, respectively (n=8, P<0.01), as well as left ventricular remodeling. NAC treatment for 2 weeks also significantly reduced the MCP-1 mRNA and protein levels by 52 and 60%, respectively (n=4-8, both P<0.01), but had no effect on blood pressure. In the rats with AC at 2 weeks, when MCP-1 expression and inflammation changes were overt, immunoblotting with phospho-specific antibodies revealed that extracellular regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK), but not p38 mitogen-activated protein kinase, were activated. NAC administration attenuated JNK activation, but had no effect on ERK. Our results suggest that increased ROS production may play an important role in the increased expression of MCP-1 in pressure overload-induced cardiac remodeling. JNK is likely involved in the signaling pathway.
Molecular Medicine Reports 03/2012; 5(6):1491-6. · 0.42 Impact Factor
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ABSTRACT: Atrial fibrillation (AF) is a common disease with a poorly understood pathophysiological mechanism. Increasing evidence indicates that AF may be associated with immunologic inflammation responses, but it remains unclear whether activation of peripheral blood CD3(+) T-lymphocytes plays a role in the pathogenesis of AF. The aim of this study was to evaluate this phenomenon. Fifty paroxysmal AF patients and 56 persistent AF patients who underwent successful electrical cardioversion were enrolled. The percentages of CD69 and human leukocyte antigen DR (HLA-DR) positive peripheral blood CD3(+) T-lymphocytes, which indicate T-lymphocyte activation, were examined by flow cytometric analysis in the patients and 51 healthy controls. The patient groups had higher levels of CD69 and HLA-DR than the healthy controls. During the 3-month follow-up, 37 patients had recurrence of AF (recurrence group) and 50 patients remained in sinus (sinus group). The CD69 and HLA-DR levels in the sinus group were all significantly down-regulated at follow-up compared with before cardioversion. However, there were no statistically significant differences between the CD69 and HLA-DR levels in the recurrence group at follow-up and before cardioversion. Our findings suggest that activation of peripheral blood CD3(+) T-lymphocytes was associated with AF, and might be a diagnostic or therapeutic marker.
International Heart Journal 01/2012; 53(4):221-4. · 1.16 Impact Factor
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ABSTRACT: Atherosclerosis is a progressive disease characterized by a series of inflammatory responses in the large and medium arteries. Th17 cells, a distinct T cell lineage which has recently been identified, have a proinflammatory role and are implicated in many inflammatory conditions in humans and mice. The present study was designed to assess whether Th17 cells are associated with human coronary atherosclerosis.
Flow cytometry was used to examine Th17 cell frequencies in patients with coronary atherosclerosis and in healthy individuals. ELISA and real-time RT-PCR were performed to investigate circulating interleukin (IL)-17 (the signature cytokine of Th17 cells) and IL-8 (the cytokine induced by IL-17) protein and mRNA levels.
Significantly increased Th17 cell frequencies are observed in patients with coronary artery disease compared to healthy controls. The protein and mRNA levels of IL-17 and IL-8 are also significantly elevated in patients with atherosclerosis compared to healthy volunteers. Furthermore, mRNA levels of IL-17 and IL-8 are correlated with each other and with peripheral neutrophil counts.
Our findings indicate that Th17 cells and their signature cytokine are involved in the process of atherogenesis. These data suggest that Th17 cells link T cell activity with neutrophilic inflammation in atherosclerosis.
Scandinavian cardiovascular journal: SCJ 02/2011; 45(1):54-61. · 1.07 Impact Factor
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ABSTRACT: GIRK4 has been shown to be a subunit of I(KACh), and the use of GIRK4 in human atrial myocytes to treat arrhythmia remains an important research pursuit. Adenovirus-delivered small hairpin RNA (shRNA) has been used to mediate gene knockdown in mouse cardiocytes, yet there is no information on the successful application of this technique in human cardiocytes. In the current study, we used a siRNA validation system to select the most efficient sequence for silencing GIRK4. To this end, adenovirus-delivered shRNA, which expresses this sequence, was used to silence GIRK4 expression in human atrial myocytes. Finally, the feasibility, challenges, and results of silencing GIRK4 expression were evaluated by RT-PCR, western blotting, and the voltage-clamp technique. The levels of mRNA and protein were depressed significantly in cells infected by adenovirus-delivered shRNA against GIRK4, approximately 86.3% and 51.1% lower than those cells infected by adenovirus-delivered nonsense shRNA, respectively. At the same time, I(KACh) densities were decreased 53% by adenovirus-delivered shRNA against GIRK4. In summary, adenovirus-delivered shRNA against GIRK4 mediated efficient GIRK4 knockdown in human atrial myocytes and decreased I(KACh) densities. As such, these data indicated that adenovirus-delivered shRNA against GIRK4 is a potential tool for treating arrhythmia.
Molecular Biology Reports 07/2009; 36(6):1345-52. · 2.93 Impact Factor
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ABSTRACT: Although inflammatory cells contribute to immunopathogenesis of atherosclerosis, underlying molecular mechanisms remain largely undefined. Recently, it has been demonstrated in mouse model that Programmed death-1 (PD-1)/PD-1 ligand (PD-L) pathway plays a critical role in proatherogenic immune responses. Here we examined the expression of PD-1 and PD-L1 on peripheral blood mononuclear cells by flow cytometry in 76 patients with coronary artery disease (CAD), and 25 healthy volunteers. The expression of PD-1 and PD-L1 is significantly down-regulated on T cells and myeloid dendritic cells (mDCs) in CAD patients than in healthy individuals, respectively. More importantly, we found that decreased PD-L1 expression on mDCs is related with the increased T cell immune responses in CAD patients. In addition, stimulation of PD-L1 expression in vitro could attenuate the stimulatory ability on allogeneic T cell proliferation and its cytokine production, including IFN-gamma and IL-2, and also influence the production of IL-10 and IL-12 by mDCs. Taken together, we can draw a conclusion that PD-1/PD-L1 pathway plays a key role in the regulation of proatherogenic T cell immunity by intervening antigen presenting cell (APC)-dependent T cell activation, which associates with pro-inflammatory or anti-inflammatory cytokine production, and further studies need gain insight into that this pathway represents a strategy of immunotherapy for atherosclerosis.
Journal of Molecular and Cellular Cardiology 12/2008; 46(2):169-76. · 5.17 Impact Factor
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ABSTRACT: PROBLEM PRESENTED: A novel study of catheter ablation of the right pulmonary artery ganglionated plexi (RPA GP) to reduce atrial fibrillation (AF) originating in the pulmonary veins (PVs) is presented. STUDIES UNDERTAKEN: In 20 dogs, atrial effective refractory periods (AERPs), PVERP, and the dispersion of AERP (dAERP) were measured at baseline during RPA GP stimulation and after ablation. Programmed stimulation and burst stimulation protocols were performed at 4 distal PVs to measure the percentage of AF induced before and after ablation. RESULTS: Stimulation of the RPA GP shortened AERP (116 +/- 16 vs 130 +/- 10 milliseconds, P < .01) and PVERP (122 +/- 14 vs 136 +/- 12 milliseconds, P < .01), and increased dAERP (31 +/- 6 vs 23 +/- 6 milliseconds, P < .01). However, the above indices revealed an adverse change after excision (AERP, 138 +/- 7 vs 130 +/- 10 milliseconds; PVERP, 146 +/- 18 vs 136 +/- 12 milliseconds; and dAERP, 19 +/- 5 vs 23 +/- 6 milliseconds; P < .05). Furthermore, the percentage of AF induced from PVs was significantly reduced with vagosympathetic stimulation (40% vs 90%, P < .01). CONCLUSIONS: Ablation of the RPA GP changes the electrophysiologic properties of both the atria and the PVs and decreases AF inducibility arising from the PVs.
Journal of electrocardiology 43(4):367-72. · 1.08 Impact Factor
