Title

Combinatorial Effects of a NADPH Oxidase Peptide Inhibitor and a Mitochondrial Targeted Peptide Antioxidant in Treatment of Myocardial Ischemia/Reperfusion (MI/R) Injury

Date of Award

2015

Degree Type

Thesis

Degree Name

Master of Science (MS)

First Advisor

Lindon Young, PhD

Second Advisor

Robert Barsotti, PhD

Third Advisor

Ruth Borghaei, PhD

Fourth Advisor

Marcus Bell, PhD

Abstract

Myocardial ischemia/reperfusion (MI/R) injury results in cardiac contractile dysfunction, and increased cell death principally due to the reperfusion of blood following ischemia. This injury is initiated, in part, by a decrease in endothelial derived nitric oxide bioavailability and an increase in reactive oxygen species (ROS). Two key sources ofROS are NADPH oxidase and damaged mitochondria. We've shown that gp91 ds-tat, a NADPH oxidase assembly inhibitor peptide and SS-31, a mitochondrial targeted antioxidant peptide, dose dependently improved post-reperfused left ventricular developed pressure (L VDP) and reduced infarct size in isolated rat hearts subjected to I (30min)/R (45min). This led us to the question, whether the combinatorial effects of low dose gp91 ds-tat (5 µM) and SS-31 (10 µM) would act synergistically to improve LVDP and reduce infarct size compared to the independent effects of each peptide and untreated control? Our data show that the combination of gp91 ds-tat (5 µM) and SS-31 (10 µM)(n=10) improved post-reperfused LVDP by 70 ± 6% of baseline and reduced infarct size (IS) to 28 ± 9% compared to control (42 ± 8% ofbaseline, n=8; 42 ± 5% IS) and to SS-31 10 µM (37 ± 6% of baseline, n=8; 40 ± 10% IS); gp91 ds-tat 5µM (47 ± 7% of baseline, n=7; 30 ± 5% IS). Our study showed that the combinatorial use oflow dose gp91ds-tat and SS-31 attenuated MIIR injury by reducing infarct size and improving post-reperfused cardiac function than either agent alone. The data suggest that gp9lds-tat and SS-31 has a synergistic effect in cardiac function when used in combination but an additive effect for infarct size. Our data suggests that inhibition of NADPH oxidase and mitochondrial-derived ROS may provide better cardioprotection.

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