The Ras antagonist farnesylthiosalicylic acid ameliorates experimental myocarditis in the rat.
BACKGROUND
Myocarditis is an inflammatory disorder of the heart in which T lymphocytes have a central role. No effective treatment is currently at hand for management of the myocarditis. Lymphocyte function requires the active signal transducer Ras. We thus hypothesized that S-farnesylthiosalicylic acid (FTS), a synthetic small molecule that detaches Ras from the inner cell membrane and induces its rapid degradation, will attenuate experimental autoimmune myocarditis (EAM).


RESULTS
Two groups of Lewis rats were induced to develop EAM by immunization with porcine cardiac myosin. Group A received 5 mg/kg of FTS, and group B received phosphate-buffered saline (PBS) according to two protocols: FTS or PBS was given 2 days before myosin immunization in protocol 1 and FTS or PBS was given 14 days after myosin immunization in protocol 2. FTS significantly suppressed myocarditis, and this effect was accompanied by a reduction in myosin-specific cellular and humoral immune responses. In the longer regimen, FTS treatment for 6 weeks was associated with preservation of myocardial function made evident by echocardiography. In vitro, FTS significantly attenuated the proliferation of lymphocytes from untreated myocarditic rats to myosin.


CONCLUSIONS
FTS is effective in suppressing the progression of EAM and its consequent functional myocardial dysfunction. The effect may be mediated by suppression of the cellular and humoral responses to myosin.
Pando
Rakefet
R
Department of Cardiology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Barshack
Iris
I
Raz
Alon
A
Luboshits
Galia
G
Haklai
Ronit
R
Maysel-Auslender
Sofia
S
Kloog
Yoel
Y
Keren
Gad
G
George
Jacob
J
D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005204:Farnesol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D009205:Myocarditis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D009206:Myocardium / Q000276:immunology / Q000473:pathology; D009218:Myosins / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D012459:Salicylates / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013552:Swine / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D018631:ras Proteins / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D012459:Salicylates; C093323:farnesylthiosalicylic acid; D005204:Farnesol; D009218:Myosins; D018631:ras Proteins