Author ORCID Identifier

orcid.org/0000-0001-9425-0403

Defense Date

2017

Document Type

Thesis

Degree Name

Master of Science

Department

Physiology and Biophysics

First Advisor

Anindita Das

Abstract

The miR-17- 92 cluster is necessary for cell proliferation and development of the cardiovascular system. Deletion of this cluster leads to death in neonatal mice. The role of this cluster still needs to be defined following ischemia and reperfusion. Methods and Results: Adult male mice were injected with Tamoxifen- was to induce inducible cardiac-specific miR-17- 92-deficient (miR-17- 92-def: MCM:TG:miR-17- 92 flox/flox ) and wild type (WT: MCM:NTG:miR-17-92 flox/flox ) mice were subjected to 30 minutes of myocardial ischemia via left anterior descending coronary artery ligation followed by reperfusion for 24 hours. Post I/R survival (48%) and ejection fraction were reduced, while myocardial infarct size enlarged in miR-17- 92-deficient mice as compared to WT mice (survival: 71%). Necrosis (trypan blue staining) and apoptosis (TUNEL assay) both were higher in adult cardiomyocytes isolated from miR-17- 92-deficient mice as compared to WT mice subjected to simulated ischemia/reoxygenation with a concomitant reduction of mitochondrial membrane potential (JC1 staining). The electron transport chain was compromised through dysregulation of glutamate+malate as complex I substrate and malate dehydrogenase in the hearts of miR-17- 92-deficient mice compared to WT. After 4 hours of reperfusion, PTEN expression, a downstream target of miR-20A, increased, while phosphorylation of AKT reduced in the hearts of miR-17- 92-deficient mice in comparison to WT. The induced knockdown of cardiac miR-17- 92 increases myocardial I/R injury by ceasing suppression of PTEN, leading to decreased concentrations of AKT and mitochondrial dysfunction. These results suggest that innovative therapeutic strategies can focus on genetic upregulation of miR-17- 92 in patients with coronary artery disease.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

7-7-2017

Available for download on Saturday, July 07, 2018

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