The time course of tumor necrosis factor-alpha, inducible nitric oxide synthase and vascular endothelial growth factor expression in an experimental model of chronic myocardial infarction in rats

An injury to the heart due to myocardial infarction may progress to heart f ailure. Among the cytokines and growth factors whose interactions promote r emodeling of the heart, increased expression of tumor necrosis factor (TNF) -alpha, inducible nitric oxide synthase (iNOS) and vascular endothelial gro wth factor (VEGF) has been found. However, little is known about the sequen ce of gene expression during the progression of heart injury. In the presen t study, male Sprague-Dawley rats were used for experimental myocardial inf arction performed by ligation of the left anterior descending coronary arte ry. TNF-alpha, iNOS and VEGF expression was assessed by reverse transcripti on polymerase chain reaction. Localization of TNF-alpha, VEGF and iNOS prot ein was assessed by immunohistochemistry. An in vitro proliferation (BrdU i ncorporation) and differentiation (tube formation) assay of human umbilical vein endothelial cells was performed. The expression of TNF-alpha, iNOS, V EGF(164) and VEGF(188) was observed during the whole period after myocardia l infarction (on days 1, 4, 11, 28 and 40), whereas VEGF(120) was found onl y on day 1 and 4. The most intense immunostaining for TNF-alpha was observe d at the border zone. The iNOS immunostaining was initially located in the endothelium, whereas later it was also present in the walls of larger vesse ls. 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 in cubation) and antiangiogenic (high TNF-alpha concentration, long period of incubation) effects of TNF-alpha. The expression of TNF-alpha and iNOS gene s with the concomitant occurrence of a decrease in VEGF(120), VEGF188 and V EGF164 protein could be related to insufficient angiogenesis and may sugges t the possible involvement of these events in remodeling after myocardial i nfarction. Copyright (C) 2001 S. Karger AG, Basel.