Effects of CXCR4 gene transfer on cardiac function after ischemia-reperfusion injury.
Acute coronary occlusion is the leading cause of death in the Western world. There is an unmet need for the development of treatments to limit the extent of myocardial infarction (MI) during the acute phase of occlusion. Recently, investigators have focused on the use of a chemokine, CXCL12, the only identified ligand for CXCR4, as a new therapeutic modality to recruit stem cells to individuals suffering from MI. Here, we examined the effects of overexpression of CXCR4 by gene transfer on MI. Adenoviruses carrying the CXCR4 gene were injected into the rat heart one week before ligation of the left anterior descending coronary artery followed by 24 hours reperfusion. Cardiac function was assessed by echocardiography couple with 2,3,5-Triphenyltetrazolium chloride staining to measure MI size. In comparison with control groups, rats receiving Ad-CXCR4 displayed an increase in infarct area (13.5% +/- 4.1%) and decreased fractional shortening (38% +/- 5%). Histological analysis revealed a significant increase in CXCL12 and tumor necrosis factor-alpha expression in ischemic area of CXCR4 overexpressed hearts. CXCR4 overexpression was associated with increased influx of inflammatory cells and enhanced cardiomyocyte apoptosis in the infarcted heart. These data suggest that in our model overexpressing CXCR4 appears to enhance ischemia/reperfusion injury possibly due to enhanced recruitment of inflammatory cells, increased tumor necrosis factor-alpha production, and activation of cell death/apoptotic pathways.
Chen
Jiqiu
J
Mount Sinai School of Medicine, New York, NY 10029, USA.
Chemaly
Elie
E
Liang
Lifan
L
Kho
Changwon
C
Lee
Ahyoung
A
Park
Jaeho
J
Altman
Perry
P
Schecter
Alison D
AD
Hajjar
Roger J
RJ
Tarzami
Sima T
ST
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D054377:Chemokine CXCL12 / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006321:Heart / Q000187:drug effects*; D006335:Heart Injuries / Q000473:pathology; D006801:Humans; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D019718:Receptors, CXCR4 / Q000235:genetics*; D015427:Reperfusion Injury; D013778:Tetrazolium Salts / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D013778:Tetrazolium Salts; D014409:Tumor Necrosis Factor-alpha; C009591:triphenyltetrazolium