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

Abstract

TNF-alpha 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-alpha production and cell toxicity, and to improve experimental models mediated by TNF-alpha (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-alpha 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-alpha 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.

• Authors: Jacob George, Simon Biner, Pnina Keren, Iris Barshack, Iris Goldberg, Jack Sherez, Alexander Levitzki, Gad Keren, Arie Roth
• Journal: Experimental and molecular pathology (Exp Mol Pathol) Vol. 74 Issue 3 Pg. 314-8 (Jun 2003) ISSN: 0014-4800 [Print] Netherlands
• PMID: 12782020 (Publication Type: Journal Article)

Chemical References

• Tumor Necrosis Factor-alpha
• Tyrphostins
• AG 556
• Peroxidase
• Protein-Tyrosine Kinases

Topics

• Animals
• Disease Models, Animal
• Echocardiography
• Heart (drug effects, physiology)
• Heart Ventricles (drug effects, metabolism, pathology)
• Immunohistochemistry
• Injections, Intraperitoneal
• Male
• Myocardial Infarction (drug therapy, metabolism, pathology)
• Myocardium (metabolism, pathology)
• Peroxidase (metabolism)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Rats
• Rats, Wistar
• Spleen (cytology, drug effects)
• Tumor Necrosis Factor-alpha (metabolism)
• Tyrphostins (administration & dosage, therapeutic use)
• Ventricular Remodeling (drug effects)