Date of Award

2015

Degree Type

Thesis

Degree Name

Master of Science (MS)

First Advisor

Lindon Young, PhD, Chairperson

Second Advisor

Qian Chen, PhD

Third Advisor

Robert Barsotti, PhD

Fourth Advisor

Marcus Bell, PhD

Abstract

Acute myocardial infarction (MI) remains a leading cause of morbidity and mortality worldwide. Accompanying MI is myocardial ischemia/reperfusion (MI/R) injury, which results in cardiac contractile dysfunction and additional myocardial cell death. MI/R injury is initiated in part by mitochondrial-derived reactive oxygen species due to mitochondrial membrane potential collapse and uncoupling of the electron transport chain, which may be due to mitochondrial fission in MI/R. Mitochondrial fission is in turn associated with shortening/fragmentation of mitochondria, decreased ATP production, and is thought to promote cardiac contractile dysfunction and post-reperfused cardiomyocyte loss, leading to increased infarct size. Therefore, inhibiting mitochondrial fission may be an effective new strategy to salvage injured cardiomyocytes during MI/R. Dynamin related protein 1 (Drp1) is a cytosolic GTPase that promotes mitochondrial fission via interaction with various outer mitochondrial membrane proteins. Mdivi-1 (MW= 353.22 g/mol), a mitochondrial fission inhibitor that acts by selectively inhibiting Drp1 GTPase activity, was used to test this strategy. Isolated perfused rat hearts subjected to 30 min ischemia and 90 min reperfusion exhibited significantly higher infarct size 46% ± 3% (n=9) compared to sham hearts (minimal infarct size), which did not undergo I/R. Administration of Mdivi-1 (25 µM) for 5 min following ischemia significantly reduced infarct size to 24% ± 2% (n=7), as compared to control 1/R heatis (p< 0.01). Moreover, control I/R hearts showed significantly compromised peak rates of rise in the first derivative of left ventricular developed pressure ( +dP/dtmax) of 656.98 ± 90.02 mmHg/s and left ventricular developed pressure (LVDP) of 35.36 ± 5.06 mmHg compared to sham hearts (+dP/dtmax of 1998.69 ± 195.87 mmHg/s and LVDP of 76.69 ± 9.12 mmHg) at the end of the experimental protocol (both p<0.01). By contrast, Mdivi-1 treatment significantly improved +dP/dtmax to 1101.83 ± 132.24 mmHg/s, LVDP to 49.85 ± 2.69 mmHg, compared to untreated control I/R hearts at the end of reperfusion (both p<0.05). These results suggest that inhibition of mitochondrial fission may be an effective strategy to mitigate heart injury in MI patients.

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