TY - JOUR
T1 - Effect of tumor necrosis factor-alpha on endothelial and inducible nitric oxide synthase messenger ribonucleic acid expression and nitric oxide synthesis in ischemic and nonischemic isolated rat heart
AU - Paz, Yosef
AU - Frolkis, Inna
AU - Pevni, Dimitri
AU - Shapira, Itzhak
AU - Yuhas, Yael
AU - Iaina, Adrian
AU - Wollman, Yoram
AU - Chernichovski, Tamara
AU - Nesher, Nahum
AU - Locker, Chaim
AU - Mohr, Rephael
AU - Uretzky, Gideon
N1 - Funding Information:
This study was supported by the Research Fund of the Department of Thoracic and Cardiovascular Surgery, Sourasky Tel-Aviv Medical Center, Israel.
PY - 2003/10/1
Y1 - 2003/10/1
N2 - OBJECTIVES: The present study aimed to investigate the influence of endogenous tumor necrosis factor-alpha (TNF-α) that was synthesized during ischemia and exogenous TNF-α on endothelial and inducible nitric oxide synthase (eNOS and iNOS) messenger ribonucleic acid (mRNA) expression and nitric oxide (NO) production in the isolated rat heart. BACKGROUND: Tumor necrosis factor-α is recognized as being a proinflammatory cytokine with a significant cardiodepressant effect. One of the proposed mechanisms for TNF-α-induced cardiac contractile dysfunction is increased NO production via iNOS mRNA upregulation, but the role of NO in TNF-α-induced myocardial dysfunction is highly controversial. METHODS: Isolated rat hearts studied by a modified Langendorff model were randomly divided into subgroups to investigate the effect of 1-h global cardioplegic ischemia or the effect of 1-h perfusion with exogenous TNF-α on the expression of eNOS mRNA and iNOS mRNA and on NO production. RESULTS: After 1 h of ischemia, there were significant increases in TNF levels in the effluent (from hearts), and eNOS mRNA expression had declined (from 0.91 ± 0.0g to 0.68 ± 0.19, p < 0.001); but there were no changes in iNOS mRNA expression, and NO was below detectable levels. Perfusion of isolated hearts with TNF-a had a cardiodepressant effect and decreased eNOS mRNA expression to 0.67 ± 0. 04 (p < 0.002). Inducible nitric oxide synthase mRNA was unchanged, and NO was below detectable levels. CONCLUSIONS: We believe this is the first study to directly show that TNF-α does not increase NO synthesis and release but does downregulate eNOS mRNA in the ischemic and nonischemic isolated rat heart.
AB - OBJECTIVES: The present study aimed to investigate the influence of endogenous tumor necrosis factor-alpha (TNF-α) that was synthesized during ischemia and exogenous TNF-α on endothelial and inducible nitric oxide synthase (eNOS and iNOS) messenger ribonucleic acid (mRNA) expression and nitric oxide (NO) production in the isolated rat heart. BACKGROUND: Tumor necrosis factor-α is recognized as being a proinflammatory cytokine with a significant cardiodepressant effect. One of the proposed mechanisms for TNF-α-induced cardiac contractile dysfunction is increased NO production via iNOS mRNA upregulation, but the role of NO in TNF-α-induced myocardial dysfunction is highly controversial. METHODS: Isolated rat hearts studied by a modified Langendorff model were randomly divided into subgroups to investigate the effect of 1-h global cardioplegic ischemia or the effect of 1-h perfusion with exogenous TNF-α on the expression of eNOS mRNA and iNOS mRNA and on NO production. RESULTS: After 1 h of ischemia, there were significant increases in TNF levels in the effluent (from hearts), and eNOS mRNA expression had declined (from 0.91 ± 0.0g to 0.68 ± 0.19, p < 0.001); but there were no changes in iNOS mRNA expression, and NO was below detectable levels. Perfusion of isolated hearts with TNF-a had a cardiodepressant effect and decreased eNOS mRNA expression to 0.67 ± 0. 04 (p < 0.002). Inducible nitric oxide synthase mRNA was unchanged, and NO was below detectable levels. CONCLUSIONS: We believe this is the first study to directly show that TNF-α does not increase NO synthesis and release but does downregulate eNOS mRNA in the ischemic and nonischemic isolated rat heart.
UR - http://www.scopus.com/inward/record.url?scp=10744220279&partnerID=8YFLogxK
U2 - 10.1016/S0735-1097(03)00992-6
DO - 10.1016/S0735-1097(03)00992-6
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AN - SCOPUS:10744220279
VL - 42
SP - 1299
EP - 1305
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
SN - 0735-1097
IS - 7
ER -