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
Master of Science (MS)
Lindon Young, PhD
Robert Barsotti, PhD
Ruth Borghaei, PhD
Marcus Bell, PhD
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.
Patel, Harsh, "Combinatorial Effects of a NADPH Oxidase Peptide Inhibitor and a Mitochondrial Targeted Peptide Antioxidant in Treatment of Myocardial Ischemia/Reperfusion (MI/R) Injury" (2015). PCOM Biomedical Studies Student Scholarship. 100.