Inhibition of Protein Phosphatase 1 by Inhibitor-2 Gene Delivery Ameliorates Heart Failure Progression in Genetic Cardiomyopathy.
From: Department of Molecular Cardiovascular Biology, Yamaguchi University School of Medicine, 1-1-1 Minami-Kogushi, Ube 755-8505, Japan.
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
- Publish Date: Jun 2006
- ISSN: 1530-6860
- Volume: 20
- Issue: 8
- Pages: 1197-9
- Medium: Internet
- Language: English
- Citation (JAMA): Yamada Michio, Ikeda Yasuhiro, Yano Masafumi, et al. Inhibition of Protein Phosphatase 1 by Inhibitor-2 Gene Delivery Ameliorates Heart Failure Progression in Genetic Cardiomyopathy.. FASEB J. Jun 2006;20:1197-9
Abstract
The type 1 protein phosphatase (PP1) has been reported to be overactivated in the failing heart, leading to a depression in cardiac function. We investigated whether in vivo PP1 inhibition by myocardial gene transfer of inhibitor-2 (INH-2), an endogenous PP1 inhibitor, alleviates heart failure (HF) progression in the cardiomyopathic (CM) hamster, a well-established HF model. Adenoviral INH-2 gene delivery improved % fractional shortening of the left ventricle (LV) accompanied by reduced chamber size at 1 wk. In vivo myocardial INH-2 gene delivery induced an increase in cytosolic PP1 catalytic subunit alpha (PP1Calpha) without inducing the corresponding increase in cytosolic PP1 activity. On the other hand, INH-2 delivery induced a decrease in microsomal PP1Calpha, resulting in a preferential decrease in microsomal PP1 activity, thereby increasing in phospholamban phosphorylation at Ser16. INH-2 gene transfer alleviated brain natriuretic peptide expression, presumably reflecting improved cardiac function. Moreover, adeno-associated virus-mediated INH-2 gene delivery significantly extended the survival time for 3 mo. These results indicate that increased PP1 activity is an exacerbating factor during progression of genetic cardiomyopathy and modulation of PP1 activity by INH-2 provides a potential new treatment for HF without activating protein kinase A signaling in cardiomyocytes.
Mesh Headings (Keywords): Animals, Cardiac Output, Low, Cardiomyopathy, Dilated, Cricetinae, Dependovirus, Disease Progression, Genetic Vectors, Male, Myocardium, Myocytes, Cardiac, Phosphoprotein Phosphatases, Protein Phosphatase 1, Proteins, Rats, Rats, Wistar, Survival Analysis, Transduction, Genetic, Ventricular Function, Left
Check for Full Text / PubMed Unique Identifier (PMID): 16627625
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