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.
|School:||University of Cincinnati|
|Department:||Molecular, Cellular and Biochemical Pharmacology|
|School Location:||United States -- Ohio|
|Source:||DAI-B 79/10(E), Dissertation Abstracts International|
|Keywords:||Cardiac inotropy, Congestive heart failure, Gene therapy, Inhibitor-1, Phospholamban, Protein phosphatase 1|
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