Comparison of the effects of myristrolated and transactivating peptide (TAT) conjugated mitochondrial fission peptide inhibitor (P110) in myocardial ischemia/reperfusion (I/R) injury

Philadelphia

During myocardial I/R, cardiac mitochondrial fission-fusiondynamics are altered towards mitochondrial fission which during I/R is associated with a shortening of mitochondria, decreased ATP production, and increased reactive oxygen species, factors known to promote cardiomyocyte death. Therefore, inhibiting mitochondrial fission may be a strategy to salvage damaged cardiac myocytes during I/R and limit infarct size. Given that cell membrane permeability of peptides is crucial for efficacy, we compared theeffects of a novel mitochondrial fission peptide inhibitor, P110 (DLLPRGT) that was conjugated to either a TAT carrier peptide YGRKKRRQRRR-GG-DLLPRGT (MW=2427 g/mol) or myristic acid myr-DLLPRGT (MW=981 g/mol) to determine which of these peptide formulations would be more potent to attenuate cardiac contractile dysfunction and infarct size in isolated perfused rat hearts subjected to I (30 min)/R (90 min). We found that myr-P110 (1 M; n=6) given for 10 min before ischemia and for 20 min post-reperfusion, significantly restored the maximal rate of left ventricular developed pressure (dP/dtmax) to 49 ± 7% compared to TAT-conjugated P110 (1 M; n=6) and untreated controls (n=9), which only recovered to 26 ± 5% and 28 ± 4% of baseline values at 90 min post-reperfusion, respectively (p<0.05). Myr-P110 also significantly reduced infarct size to 28± 2% compared to controls which had an infarct size of 46±3% (p<0.01). Whereas, TAT-conjugated P110 had an infarct size of 35 ± 3% and was not statistically different from controls using ANOVA analysis. Preliminary results suggest myr-P110 would be a more effective formulation to salvage heart tissue after myocardial infarction.