title: MCP-1 induces cardioprotection against ischaemia/reperfusion injury: role of reactive oxygen species.
abstract: OBJECTIVE
  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).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cardiovascular Medicine, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Morimoto
authors.forename: Masamichi
authors.initials: M
authors.lastname: Hirose
authors.forename: Masafumi
authors.initials: M
authors.lastname: Takahashi
authors.forename: Masanori
authors.initials: M
authors.lastname: Kawaguchi
authors.forename: Hirohiko
authors.initials: H
authors.lastname: Ise
authors.forename: Pappachan E
authors.initials: PE
authors.lastname: Kolattukudy
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Yamada
authors.forename: Uichi
authors.initials: U
authors.lastname: Ikeda
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D002316:Cardiotonic Agents / Q000378:metabolism*; D015687:Cell Hypoxia; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D007527:Isoenzymes / Q000378:metabolism; D054086:KATP Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D024723:Ventricular Myosins / Q000235:genetics; D017725:Ventricular Pressure
chemical_list: D002316:Cardiotonic Agents; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D007527:Isoenzymes; D054086:KATP Channels; D026902:Potassium Channel Blockers; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D019255:NADPH Oxidases; D024723:Ventricular Myosins; D018995:Myosin Heavy Chains