MCP-1 induces cardioprotection against ischaemia/reperfusion injury: role of reactive oxygen species.
ABSTRACT Monocyte chemoattractant protein-1 (MCP-1: CCL2) has been demonstrated to be involved in the pathophysiology of ischaemic heart disease; however, the precise role of MCP-1 in ischaemia/reperfusion (I/R) injury is controversial. Here, we investigated the role of cardiac MCP-1 expression on left ventricular (LV) dysfunction after global I/R in Langendorff-perfused hearts isolated from transgenic mice expressing the mouse JE-MCP-1 gene under the control of the alpha-cardiac myosin heavy chain promoter (MHC/MCP-1 mice).
In vitro experiments showed that MCP-1 prevented the apoptosis of murine neonatal cardiomyocytes after hypoxia/reoxygenation. I/R significantly increased the mRNA expression of MCP-1 in the Langendorff-perfused hearts of wild-type mice. Cardiac MCP-1 overexpression in the MHC/MCP-1 mice improved LV dysfunction after I/R without affecting coronary flow; in particular, it ameliorated LV diastolic pressure after reperfusion. This improvement was independent of both sarcolemmal and mitochondrial K(ATP) channels. Cardiac MCP-1 overexpression prevented superoxide generation in the I/R hearts, and these hearts showed decreased expression of the NADPH oxidase family proteins Nox1, gp91phox, and Nox3 compared with the hearts of wild-type mice. Further, superoxide dismutase activity in the hearts of MHC/MCP-1 mice was significantly increased compared with that in the hearts of wild-type mice.
These findings suggest that cardiac MCP-1 prevented LV dysfunction after global I/R through a reactive oxygen species-dependent but K(ATP) channel-independent pathway; this provides new insight into the beneficial role of MCP-1 in the pathophysiology of ischaemic heart diseases.
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ABSTRACT: Myocardial contractile dysfunction is a major consequence of septic shock, which is mainly mediated by nuclear factor-kappa B (NF-кB)-dependent production of inflammatory mediators in the heart. A novel zinc-finger protein, MCP-1-induced protein (MCPIP), is thought to have NF-кB inhibitory activity in certain cell cultures, but its pathophysiological consequence in vivo remains undefined. This study aims to clarify whether the anti-inflammatory potency of MCPIP contribute to amelioration of septic myocardial inflammation and dysfunction in vivo. Transgenic mice (TG) with cardiac-specific expression of MCPIP and their littermate wild-type (WT) controls were challenged with Escherichia coli LPS (10mg/kg ip) and myocardial function was assessed 18 h later using echocardiography. LPS administration markedly deteriorated myocardial contractile function evidenced by reduction of the percentage of left ventricular fractional shortening, which was significantly attenuated by myocardial expression of MCPIP. MCPIP TG mice exhibited a markedly reduced myocardial inflammatory cytokines, less of iNOS expression and peroxynitrite formation, decreased caspase-3/7 activities and apoptotic cell death compared with LPS-treated WT mice. Activation of cardiac NF-кB observed in LPS-challenged WT mice was suppressed by the presence of MCPIP, as evidenced by decreased phosphorylation of IкB kinase (IKKα/β), reduced degradation of the cytosolic IкBα, and decreased nuclear translocation of NF-кB p65 subunit and its target DNA-binding activity. These results suggest that MCPIP has therapeutic values to protect heart from inflammatory pathologies, possibly through inhibition of IкB kinase complex, leading to blockade of NF-кB activation, and subsequently, attenuation of the proinflammatory state and nitrosative stress in the myocardium.Journal of Molecular and Cellular Cardiology 08/2011; 51(2):177-86. · 5.15 Impact Factor
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ABSTRACT: The role of reactive oxygen species (ROS) in UVB-induced apoptosis has been established, but the molecular mechanisms of their production in response to UVB irradiation in keratinocytes are not well understood. In this study, we demonstrate that levels of BLT2, a low-affinity leukotriene B(4) receptor, and its ligands (LTB(4) and 12(S)-HETE) are greatly increased by UVB irradiation and are responsible for the UVB-induced ROS generation in human keratinocytes. Blockade of BLT2 with a BLT2-specific antagonist, LY255283, or with siBLT2 attenuated ROS production and apoptotic cell death detected by a number of criteria. Moreover, we found that the NADPH oxidase family protein Nox1 lies downstream of BLT2 and mediates UVB-induced ROS production and apoptosis. Topical treatment of mouse epidermal skin with LY255283 gave significant protection against UVB-induced sunburn-associated apoptotic damage. Finally, when BLT2-overexpressing transgenic mice were irradiated with UVB, we observed more extensive skin apoptosis. Taken together, our results demonstrate that a "BLT2-Nox1"-linked pathway has a crucial role in UVB-induced ROS generation and mediates apoptosis in human keratinocytes.Journal of Investigative Dermatology 04/2010; 130(4):1095-106. · 6.19 Impact Factor
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ABSTRACT: AIMS: Proliferation of pulmonary arterial smooth muscle cells (PASMCs) is one histological sign of pulmonary arterial hypertension (PAH). We hypothesized that a signaling cascade from fibroblast growth factor 2 (FGF2) to plasminogen activator inhibitor 1 (PAI-1) and monocyte chemotactic protein-1 (MCP-1) via nuclear transcription factor NF-kB, play a critical role in progression of PAH, and tested this hypothesis both in vivo and in vitro using a synthetic selective NF-kB inhibitor, N-(3,5-Bis-trifluoromethyl-phenyl)-5-chloro-2-hydroxy-benzamide (IMD-0354).Methods and ResultsMonocrotaline (MCT) was injected into 75 Sprague Dawley rats. Starting at day 14 after MCT injection, we administered IMD-0354 (MCT+IMD group) or vehicle (MCT group) daily. At day 32, 65% of MCT+IMD group were alive compared to 0% of the MCT group. IMD-0354 prevented increase of right ventricular pressure, and suppressed proliferation and induced apoptosis of PASMCs. mRNA transcript levels of FGF2, PAI-1, and tissue plasminogen activator (t-PA) were lower in MCT+IMD compared to MCT. In in vitro experiments, IMD-0354 inhibited p65 translocation to the nucleus promoted by FGF2 in PASMCs. Furthermore the time courses of extracellular signal-regulated kinase (Erk) 1/2, MCP-1 and PAI-1 stimulated with FGF2 were each markedly shortened by IMD-0354. CONCLUSIONS: We speculate that the positive-feedback loop (Erk1/2 - NF-kB - MCP-1 - Erk1/2) is associated with progression of PAH by causing FGF2-induced inflammation in MCT rats. IMD-0354 has potential as a new therapeutic tool for PAH.Cardiovascular Research 04/2013; · 5.81 Impact Factor