An injury to the heart due to myocardial infarction may progress to heart failure. Among the cytokines and growth factors whose interactions promote remodeling of the heart, increased expression of tumor necrosis factor (TNF)-alpha, inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor (VEGF) has been found. However, little is known about the sequence of gene expression during the progression of heart injury. In the present study, male Sprague-Dawley rats were used for experimental myocardial infarction performed by ligation of the left anterior descending coronary artery. TNF-alpha, iNOS and VEGF expression was assessed by reverse transcription polymerase chain reaction. Localization of TNF-alpha, VEGF and iNOS protein was assessed by immunohistochemistry. An in vitro proliferation (BrdU incorporation) and differentiation (tube formation) assay of human umbilical vein endothelial cells was performed. The expression of TNF-alpha, iNOS, VEGF(164) and VEGF(188) was observed during the whole period after myocardial infarction (on days 1, 4, 11, 28 and 40), whereas VEGF(120) was found only on day 1 and 4. The most intense immunostaining for TNF-alpha was observed at the border zone. The iNOS immunostaining was initially located in the endothelium, whereas later it was also present in the walls of larger vessels. The VEGF protein was present in the border zone. No gene expression or immunostaining was detected in sham-operated rats. The in vitro experiments showed both proangiogenic (low TNF-alpha concentration, short period of incubation) and antiangiogenic (high TNF-alpha concentration, long period of incubation) effects of TNF-alpha. The expression of TNF-alpha and iNOS genes with the concomitant occurrence of a decrease in VEGF(120), VEGF(188) and VEGF(164) protein could be related to insufficient angiogenesis and may suggest the possible involvement of these events in remodeling after myocardial infarction.
Copyright 2001 S. Karger AG, Basel