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Dissertation/Thesis Abstract

Mechanistic Consequences of Cardiac Oxidative Stress
by Han, Bing, Ph.D., The Ohio State University, 2008, 283; 10630986
Abstract (Summary)

This thesis deals with understanding the mechanistic consequences of cardiac oxidative stress in non-ischemic cardiovascular complications settings including type I diabetes and cocaine related cardiovascular complications. It is intended to provide novel mechanistic insights into these complications so that specialized therapy can be developed to treat these complications. Additional components of this dissertation deals with the appropriate use of stress testing in mice in addition to basal cardiovascular function measurements.

Using a murine type 1 diabetes model we tested the hypothesis that alterations in cardiac performance were associated with myocardial oxidative stress. The data demonstrate that the mouse model of STZ induced type-1 diabetes mimics the cardiovascular abnormalities observed in clinical settings with respect to non-ischemic contractile alterations, electrophysiological abnormalities and microvascular rarefaction and that these changes are related to oxidative stress, perturbations in myocardial vascular endothelial growth factor (VEGF) isoforms and/or connexin regulation. These findings also implicate GSH depletion and/or GSSG accumulation as participants in this setting.

In subsequent investigations we observed that cardiac GSH depletion in normal mice causes increased cardiac oxidative stress and modulates cardiac performance. Using buthionine sulfoximine (BSO) cardiac GSH/GSSG was significant reduced at 24hr. Elongation of QTc and QRS, impaired diastolic performance, and increased cardiac output were observed. Moderate cardiovascular stress testing decreased cardiac contractile function and provoked an increase in arrhythmias in animals pretreated with BSO. These cardiac effects were associated with oxidative insults to key components of the contractile and electrical apparatus, such as, desmin, troponin (T), ERG and Cx43.

In addition, we investigated cocaine related acute and chronic cardiovascular dysfunction using a mouse model and explored the inter-relationship among oxidative stress, protracted cardiac abnormities and acute cardiac work load stress. Cardiovascular abnormalities were observed in murine model, similar to clinical phenomenon. Extensive dysregulation of reactive nitrogen species were observed as evidenced by increased cardiac prevalence of NOS2 and protein-3NT. These oxidant status changes were correlated to cardiac function changes, suggesting that cardiac dysfunction might be mediated by oxidative stress.

Overall, these studies demonstrate cardiac oxidative stress, in particular, GSH depletion, plays an important role in progression of cardiovascular dysfunction.

Indexing (document details)
Advisor: Bauer, John A.
Commitee: Elton, Terry S., Feldman, David S., Hoyt, Dale G., Phillips, Alistair, Wold, Loren E.
School: The Ohio State University
Department: Pharmacy
School Location: United States -- Ohio
Source: DAI-B 78/11(E), Dissertation Abstracts International
Subjects: Pharmacology
Keywords: Cardiovascular, Cocaine, Diabetes, Glutathione, Oxidative stress
Publication Number: 10630986
ISBN: 978-0-355-01297-2
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