title: Involvement of reactive oxygen species and JNK in increased expression             of MCP-1 and infiltration of inflammatory cells in pressure-overloaded rat hearts.
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.
authors.affiliation: Department of Cardiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, People's Republic of China.
authors.forename: Fujun
authors.initials: F
authors.lastname: Shang
authors.forename: Jiepin
authors.initials: J
authors.lastname: Wang
authors.forename: Xiongtao
authors.initials: X
authors.lastname: Liu
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Qiangsun
authors.initials: Q
authors.lastname: Zheng
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Xue
authors.forename: Lianyou
authors.initials: L
authors.lastname: Zhao
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D045163:Antibodies, Phospho-Specific / Q000276:immunology; D001017:Aortic Coarctation / Q000503:physiopathology; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D005786:Gene Expression Regulation; D006321:Heart / Q000503:physiopathology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D011312:Pressure; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D045163:Antibodies, Phospho-Specific; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D016166:Free Radical Scavengers; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D000111:Acetylcysteine