Tyrphostin AG-556 reduces myocardial infarct size and improves cardiac performance in the rat.
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.
George
Jacob
J
Department of Cardiology and the Cardiovascular Research Laboratory, Tel-Aviv Medical Center, Tel-Aviv, Israel. jacobg@post.tau.ac.il
Biner
Simon
S
Keren
Pnina
P
Barshack
Iris
I
Goldberg
Iris
I
Sherez
Jack
J
Levitzki
Alexander
A
Keren
Gad
G
Roth
Arie
A
D000818:Animals; D004195:Disease Models, Animal; D004452:Echocardiography; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020032:Tyrphostins / Q000008:administration & dosage / Q000627:therapeutic use*; D020257:Ventricular Remodeling / Q000187:drug effects*
D014409:Tumor Necrosis Factor-alpha; D020032:Tyrphostins; C098981:AG 556; D009195:Peroxidase; D011505:Protein-Tyrosine Kinases