Dissertation/Thesis Abstract

The Role of the Protein Phosphatase 1 Inhibitor-1 In Regulation of Murine Cardiac Physiology and Progression of Cardiomyopathy
by Pathak, Anand, Ph.D., University of Cincinnati, 2006, 357; 10857175
Abstract (Summary)

The role of the protein phosphatase 1 inhibitor-1 in the regulation of cardiac physiology and the progression of cardiomyopathy was investigated in this study. Overexpression of the active inhibitor-1 in the murine heart resulted in hyperdynamic myocardial function, linked to specific modulation in the phosphorylation levels of phospholamban, an inhibitor of the sarcoplasmic reticulum ATPase (SERCA). Inhibitor-1 expressing cardiomyocytes exhibited enhanced calcium cycling linked to reduced inhibition of SERCA by the phosphorylated phospholamban. The inhibitor-1 overexpressing mouse was also challenged with the stress of chronic pressure overload. Interestingly, inhibitor-1 expression, in this stress model, completely protected against functional decline and was associated with reduced hypertrophy. At the molecular level, increased phosphorylation of phospholamban (serine-16) persisted in banded inhibitor-1 mice.

The effects of inhibitor-1 expression were also studied as a molecular intervention in a rat model of heart failure, generated by chronic pressure overload. Therapeutic gene transfer of inhibitor-1 in failing rat hearts, resulted in restoration of cardiac function towards normal, and was also associated with increased phosphorylation of phospholamban at serine-16. All in all, these studies provide significant support for the potential of inhibitor-1, as a therapeutic target; however, more extensive studies in larger animal models and more controlled expression systems are required for further validation of inhibitor-1 as a molecular target in heart failure.

Indexing (document details)
Advisor: Kranias, Evangelia
Commitee:
School: University of Cincinnati
Department: Molecular, Cellular and Biochemical Pharmacology
School Location: United States -- Ohio
Source: DAI-B 79/10(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Pharmaceutical sciences
Keywords: Cardiac inotropy, Congestive heart failure, Gene therapy, Inhibitor-1, Phospholamban, Protein phosphatase 1
Publication Number: 10857175
ISBN: 9780438022898
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