The Effects of Myristoylated and Transactivating Peptide (TAT) Conjugated P110 in Myocardial Ischemia-reperfusion (I/R) Injury

Date of Award

2019

Degree Type

Thesis

Degree Name

Master of Science in Biomedical Sciences

First Advisor

Lindon Young, PhD

Second Advisor

Qian Chen, PhD

Third Advisor

Cathy Hatcher, PhD

Abstract

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

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