Tyrphostin AG-556 reduces myocardial infarct size and improves cardiac performance in the rat

Jacob George*, Simon Biner, Pnina Keren, Iris Barshack, Iris Goldberg, Jack Sherez, Alexander Levitzki, Gad Keren, Arie Roth

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

TNF-α is a proinflammatory cytokine, abundantly expressed after myocardial infarction. It has been suggested that it exhibits myocardial suppressive and cytotoxic effects. AG-556 is a tyrosine kinase inhibitor synthesized based on its ability to reduce TNF-α production and cell toxicity, and to improve experimental models mediated by TNF-α (i.e., peritontitis and experimental autoimmune encephalomyelitis). Daily, for 7 days, rats were injected ip with either AG-556 dissolved in DMSO or with the control vehicle. Infarct size was determined in the hearts as well as in fibrous scar formation. Cardiac TNF-α expression was evaluated by ELISA and immunohistochemistry. Functional hemodynamic parameters were evaluated employing echocardiography prior to sacrifice. AG-556 treatment reduced MI size at 7 days with a parallel effect on fibrous tissue formation. TNF-α production by splenocytes was reduced upon AG-556 treatment, whereas no differences were evident between the groups with regard to myocardial cytokine expression. AG-556 attenuated the decrease in fractional shortening at the expense of preserving end systolic diameter. AG-556 has proven beneficial in reducing myocardial infarct size and attenuated consequent hemodynamic deterioration in the rat model. If reconfirmed, AG-556 may be of potential clinical use in post-MI patients.

Original languageEnglish
Pages (from-to)314-318
Number of pages5
JournalExperimental and Molecular Pathology
Volume74
Issue number3
DOIs
StatePublished - Jun 2003
Externally publishedYes

Keywords

  • Inflammation
  • Myocardial infarct
  • Rat
  • Remodeling
  • TNF-α

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