The Time Course of Tumor Necrosis Factor-α, Inducible Nitric Oxide Synthase and Vascular Endothelial Growth Factor Expression in an Experimental Model of Chronic Myocardial Infarction in Rats

Abstract

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)-α, 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-α, iNOS and VEGF expression was assessed by reverse transcription polymerase chain reaction. Localization of TNF-α, 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-α, iNOS, VEGF₁₆₄ and VEGF₁₈₈ was observed during the whole period after myocardial infarction (on days 1, 4, 11, 28 and 40), whereas VEGF₁₂₀ was found only on day 1 and 4. The most intense immunostaining for TNF-α 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-α concentration, short period of incubation) and antiangiogenic (high TNF-α concentration, long period of incubation) effects of TNF-α. The expression of TNF-α and iNOS genes with the concomitant occurrence of a decrease in VEGF₁₂₀, VEGF₁₈₈ and VEGF₁₆₄ protein could be related to insufficient angiogenesis and may suggest the possible involvement of these events in remodeling after myocardial infarction.

Host Vascular Niche Contributes to Myocardial Repair Induced by Intracoronary Transplantation of Bone Marrow CD34+ Progenitor Cells in Infarcted Swine Heart

“…Shen et al [23] show that endothelial cells that are enriched in the neural stem cell niche could regulate neural stem cell proliferation by secreting bFGF and induce these stem cells to become neurons in vitro. However, in this study, both the mRNA and protein levels of VEGF expression were not significantly different among individual groups 2 and 6 weeks after MI, consisting of data from the pig study by Heba et al [24] showing that the expression of VEGF was upregulated within 4 days after MI. We also observed that the expression of VEGF was increased at 2 days, peaked at 7 days, and decreased thereafter in the infarcted hearts of rats (data not shown).…”

“…At the onset of MI (within 4 days), the cytokine was detected extracellularly in the border zone of myocardial infarction and locally in inflammatory infiltrates of infarcted myocardium [24], indicating that the early expression levels of bFGF were related to the degree of hypoxia and inflammatory reaction. At a later stage, however, cytokine was found mainly in vascular cells situated among fibrous tissue of the border zone [24], suggesting that the expression levels of bFGF were related mainly to the amount of surviving vascular cells. In addition, we observed in another experiment that the increase of bFGF appeared as early as 2 days, and the increase persisted for more than 2 weeks after MI in rats (data not shown), suggesting that bFGF might play an important role in the cardiac repair even at a later stage after MI.…”

Bradycardia Induces Angiogenesis, Increases Coronary Reserve, and Preserves Function of the Postinfarcted Heart

“…As previously noted, MI is associated with upregulation of VEGF, bFGF, hepatocyte growth factor, [25][26][27][28][29][30][31] and VEGF receptors Flt-1 and Flk-1 28 in the surviving myocardium. These growth factor responses promote some limited degree of angiogenesis in the infarcted heart.…”

Vascular Endothelial Growth Factor Blockade Promotes the Transition From Compensatory Cardiac Hypertrophy to Failure in Response to Pressure Overload

“…Previous studies have shown that VEGF is upregulated in myocardium in pathological conditions such as myocardial infarction, 31,32 pressure overload, 29,30 and hemodynamic overload. 33 In vitro, it has been shown that VEGF is secreted from cardiomyocytes in response to various extracellular stimuli.…”