Ras inhibition attenuates myocardial ischemia-reperfusion injury.
Myocardial injury, developed after a period of ischemia/reperfusion (I/R) results in the destruction of functional heart tissue, this being replaced by scar tissue. Intracellular signaling pathways mediating cardiomyocyte death are partially understood and involve the activation of Ras. p38-MAPK, JNK and Mst-1 are downstream effectors of Ras protein. We hypothesized that S-farnesylthiosalicylic acid (FTS), a synthetic small molecule that detaches Ras from the inner cell membrane, consequently inhibiting Ras activity, reduces I/R myocardial injury in vitro and in vivo. Wistar rat hearts were isolated, mounted on the Langendorff apparatus and subjected to ischemia (30 min, 37 degrees C) and reperfusion. During the reperfusion period, the hearts were perfused with FTS (1 microM) solution or control buffer. Left anterior descending (LAD) ligation and subsequent reperfusion was performed in two groups of Wistar rats. Rats received 5mg/kg FTS or PBS according to two protocols: (A) FTS or PBS were administered daily 7 days prior, immediately before and 14 days (every other day) after LAD occlusion or (B) every other day for 14 days post-I/R. Hearts from FTS-treated rats (Langendorff) and FTS-treated rats (protocol A) showed a significant improvement in myocardial performance and smaller scar tissue compared with the PBS group. Infarct size in the FTS-treated group was 12.7+/-2% vs. 23.7+/-4% in the PBS-treated (in vitro) group and 17.3+/-2.5% vs. 36+/-7% compared with control I/R rats (in vivo) p<0.05. These effects may be associated with the down regulation of JNK as a short-term effector and with Mst-1 in the long-term remodeling process.
The Department of Cardiology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Rakefet
R
Pando
Yelena
Y
Cheporko
Ronit
R
Haklai
Sofia
S
Maysel-Auslender
Gad
G
Keren
Jacob
J
George
Eyal
E
Porat
Alex
A
Sagie
Yoel
Y
Kloog
Edith
E
Hochhauser
D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005204:Farnesol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D006334:Heart Function Tests; D066298:In Vitro Techniques; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D012459:Salicylates / Q000008:administration & dosage / Q000494:pharmacology*; D018631:ras Proteins / Q000037:antagonists & inhibitors*
D012459:Salicylates; C093323:farnesylthiosalicylic acid; D005204:Farnesol; D018631:ras Proteins