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Updated: Jun 23, 2026
Improved Rodent Model of Myocardial Ischemia and Reperfusion Injury
Published on: March 7, 2022
Ras inhibition attenuates myocardial ischemia-reperfusion injury
Rakefet Pando1, Yelena Cheporko, Ronit Haklai
1The Department of Cardiology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Abstract:
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.
Insights
S-farnesylthiosalicylic acid (FTS) reduces heart tissue damage from ischemia/reperfusion (I/R) injury. This Ras inhibitor improved heart function and reduced scar tissue in both in vitro and in vivo models.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Pharmacology
Background:
- Ischemia/reperfusion (I/R) injury leads to significant myocardial damage and scar formation.
- Intracellular signaling pathways, including Ras activation, are implicated in cardiomyocyte death during I/R.
- Downstream effectors of Ras, such as JNK and Mst-1, play crucial roles in I/R-induced injury and cardiac remodeling.
Purpose of the Study:
- To investigate the potential of S-farnesylthiosalicylic acid (FTS) in mitigating ischemia/reperfusion (I/R) myocardial injury.
- To determine if inhibiting Ras activity with FTS can reduce cardiomyocyte death and preserve cardiac function post-I/R.
- To explore the effects of FTS on downstream signaling pathways like JNK and Mst-1 in the context of I/R injury.
Main Methods:
- Isolated Wistar rat hearts were subjected to 30 minutes of ischemia followed by reperfusion, with FTS or control buffer perfusion.
- In vivo studies involved LAD ligation and reperfusion in Wistar rats, with FTS or PBS administered via different treatment protocols (pre- and post-I/R).
- Myocardial performance, infarct size, and scar tissue formation were assessed, alongside analysis of downstream signaling effectors.
Main Results:
- FTS treatment significantly improved myocardial performance in isolated hearts compared to controls.
- In vivo studies demonstrated a marked reduction in infarct size in FTS-treated rats (17.3%) versus control I/R rats (36%).
- FTS administration led to smaller scar tissue formation and suggested down-regulation of JNK and Mst-1 signaling.
Conclusions:
- S-farnesylthiosalicylic acid (FTS) effectively reduces myocardial injury resulting from ischemia/reperfusion (I/R).
- Inhibition of Ras activity by FTS preserves cardiac function and minimizes scar tissue development post-I/R.
- FTS shows promise as a therapeutic agent for managing I/R-induced heart damage, potentially via modulation of JNK and Mst-1 pathways.
