Interaction between paracrine tumor necrosis factor-alpha and paracrine angiotensin II during myocardial ischemia

Inna Frolkis, Jacob Gurevitch, Yael Yuhas, Adrian Iaina, Yoram Wollman, Tamara Chernichovski, Yosef Paz, Menachem Matsa, Dimitri Pevni, Amir Kramer, Itzhak Shapira, Rephael Mohr

Research output: Contribution to journalArticlepeer-review

Abstract

OBJECTIVES: The purpose of this study was to explore interactions between paracrine angiotensin II (Ang-II) and tumor necrosis factor-alpha (TNF-alpha) during myocardial ischemia. BACKGROUND: Ischemic myocardium releases significant amounts of TNF-alpha. This paracrine release correlated with postischemic myocardial injury. Other studies showed myocardial protection obtained by the use of angiotensin-converting enzyme inhibitors (i.e., captopril) and the Ang-II type 1 receptor antagonist losartan after ischemia. The possibility that these agents decrease TNF-alpha synthesis has not yet been investigated. METHODS: Using the modified Langendorff model, isolated rat hearts underwent either 90 min of nonischemic perfusion (control group) or 1 h of global cardioplegic ischemia. In both groups, either captopril (360 μmol/liter) or losartan (182.2 μmol/liter) was added before ischemia. The hearts were assayed for messenger ribonucleic acid (mRNA) expression and effluent TNF-alpha levels. In addition, cardiac myocytes were incubated in cell culture with Ang-II. RESULTS: After ischemia, TNF-alpha mRNA expression intensified from 0.63 ± 0.06 (control group) to 0.92 ± 0.12 (p < 0.03), and effluent TNF-alpha levels were 711 ± 154 pg/ml. The TNF-alpha mRNA expression declined to 0.46 ± 0.07 (p < 0.01) and 0.65 ± 0.08 (p < 0.02) in captopril- and losartan-treated hearts, respectively. Effluent TNF-alpha was below detectable levels. Concentrations of TNF-alpha in supernatants of incubated cardiac myocytes treated with 10 and 50 nmol/liter of Ang-II were 206.0 ± 47.0 pg/ml and 810 ± 130 pg/ml, respectively (p < 0.004). When pretreated with 700 μmol/liter of losartan, TNF-alpha was below detectable levels. CONCLUSIONS: This study presents an original explanation for previously reported myocardial protection after ischemia, obtained by the use of captopril and losartan. These drugs reduce TNF-alpha synthesis, providing strong evidence of active interactions between paracrine TNF-alpha and Ang-II in the evolution of the ischemic cascade.

Original languageEnglish
Pages (from-to)316-322
Number of pages7
JournalJournal of the American College of Cardiology
Volume37
Issue number1
DOIs
StatePublished - 2001

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