The Effects of Myristoylated and Transactivating Peptide (TAT) Conjugated P110 in Myocardial Ischemia-reperfusion (I/R) Injury
Date of Award
Master of Science in Biomedical Sciences
Lindon Young, PhD
Qian Chen, PhD
Cathy Hatcher, PhD
During myocardial ischemia (I/R), mitochondrial dynamics are altered towards mitochondrial fission. Decreased ATP production, shortening of mitochondria, and increased reactive oxygen species during I/R are all associated with mitochondrial fission and thought 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 the effects of a novel mitochondrial fission peptide inhibitor, P110 (DLLPRGT; MW=771 g/mol) 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 µM; 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 µM 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. 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 that myr-P110 would be a more effective formulation to salvage heart tissue after myocardial infarction.
Benjamin, Israel D., "The Effects of Myristoylated and Transactivating Peptide (TAT) Conjugated P110 in Myocardial Ischemia-reperfusion (I/R) Injury" (2019). PCOM Biomedical Studies Student Scholarship. 183.