Title

Protein Kinase Beta II (PKC-βІI) inhibitor exerts cardioprotective effects in Myocardial Ischemia/Reperfusion Injury (MI/R)

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/reperfusion (I/R), the generation of reactive oxygen species (ROS) contributes to the post-reperfused cardiac injury and contractile dysfunction. Activation of Protein Kinase C beta II (PKC βII) has been associated with increased ROS release from myocardial I/R tissue, decreased endothelial-derived nitric oxide, and increased infarct size. We tested the hypothesis that using a cell permeable PKC βII peptide inhibitor (PKC βII-) (N-myr-SLNPEWNET, MW=1300 g/mol, 10μM or 20μM) will attenuate infarct size and improve post-reperfused cardiac function compared to untreated controls in isolated perfused rat hearts subjected to I(30min)/R(90 min). PKC βII- treated hearts (both 10 and 20 μM) significantly improved postreperfused cardiac function (e.g. left ventricular developed pressure [LVDP], and dP/dt max) compared to controls (all p<0.05). I/R+PKC βII inhibitor hearts (10 μM , n=7; 20 μM, n=5) exhibited a significant improvement in LVDP 66 + 8% mmHg, and dP/dt max 56 + 8%mmHg/s (20 μM) and 57±7% mmHg, 48±5% mmHg/s (10 μM) compared to control I/R hearts (n=9) that only recovered to 38±6% mmHg and 28 ±4% mmHg/s at 90 min post-reperfusion of initial baseline. Additionally, the 20 μM PKC βII- treated hearts significantly restored post-reperfused LVDP as early as 10min postreperfusion as this effect is attributed to significantly better LV end diastolic pressure compared to controls (both p<0.05). Regarding heart tissue viablity, PKC βII- treated hearts showed significant reduction in infarct size (25±3% [20 μM] and 29±3% [10 μM]) compared to controls (46±3%) [p˂0.01]). The results suggest that PKC βII- is effective in improving cardiac function and reducing infarct size and aids in clinical myocardial infarction/organ transplantation patient recovery.

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