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Effect of granulocyte-macrophage colony-stimulating factor inducer on left ventricular remodeling after acute myocardial infarction

Division of Cardiology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan

Manuscript received January 27, 2004; revised manuscript received April 12, 2004, accepted May 19, 2004.

^* Reprint requests and correspondence: Dr. Toshihisa Anzai, Division of Cardiology, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan (Email: anzai{at}cpnet.med.keio.ac.jp).

OBJECTIVES: We sought to determine the influence of granulocyte-macrophage colony-stimulating factor (GM-CSF) induction on post-myocardial infarction (MI) remodeling, especially in relation to the inflammatory response and myocardial fibrosis.

BACKGROUND: Granulocyte-macrophage colony-stimulating factor modifies wound healing by promoting monocytopoiesis and infiltration of monocytes and macrophages into injured tissue; however, the effect of GM-CSF induction on the infarct healing process and myocardial fibrosis is unclear.

METHODS: A model of MI was produced in Wistar rats by ligation of the left coronary artery. The MI animals were randomized to receive GM-CSF inducer (romurtide 200 µg/kg/day for 7 consecutive days) (MI/Ro) or saline (MI/C).

RESULTS: Echocardiographic and hemodynamic studies on day 14 revealed increased left ventricular (LV) end-diastolic dimension, decreased fractional shortening, elevated LV end-diastolic pressure, and decreased LV maximum rate of isovolumic pressure development in MI/Ro compared with MI/C. Immunoblotting showed that expression of transforming growth factor (TGF)-ß1 in the infarcted site on day 3 after MI was decreased in MI/Ro compared with MI/C. In the infarcted site, TGF-ß1, collagen type I and type III messenger ribonucleic acid (mRNA) expression on day 3, and collagen content on day 7 were reduced in MI/Ro compared with MI/C, in association with marked infarct expansion. In MI/Ro, monocyte chemoattractant protein-1 mRNA level and the degree of infiltration of monocyte-derived macrophages (ED-1-positive)were greater in the infarcted site on day 7 than those in MI/C.

CONCLUSIONS: The GM-CSF induction by romurtide facilitated infarct expansion in association with the promotion of monocyte recruitment and inappropriate collagen synthesis in the infarcted region during the early phase of MI.

Abbreviations and Acronyms   ECM = extracellular collagen matrix   GAPDH = glyceraldehyde 3-phosphate dehydrogenase   GM-CSF = granulocyte-macrophage colony-stimulating factor   LV = left ventricular/ventricle   LVEDD = left ventricular end-diastolic dimension   LVESD = left ventricular end-systolic dimension   MCP = monocyte chemoattractant protein   MI = myocardial infarction   mRNA = messenger ribonucleic acid   PCR = polymerase chain reaction   RWT = relative wall thickness   TGF = transforming growth factor

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