Display Full Text | Download Full Text
3.92 MB PDF file

Degree

PhD, University of Cincinnati, Medicine : Molecular, Cellular & Biochemical Pharmacology, 2006.

Abstract

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.

Subject Headings

Biology, Molecular

Keywords

congestive heart failure; protein phosphatase 1; inhibitor-1; phospholamban; cardiac inotropy; gene therapy

Advisor

Dr. Evangelia G. Kranias

Pages

357p.

Document number: ucin1141265235
Permalink: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1141265235

This ETD has been downloaded 1548 times (through March 2013)