Inhibition of protein phosphatase 1 by inhibitor-2 gene delivery ameliorates heart failure progression in genetic cardiomyopathy.

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.

• Authors: Michio Yamada, Yasuhiro Ikeda, Masafumi Yano, Koichi Yoshimura, Shizuka Nishino, Hidekazu Aoyama, Lili Wang, Hiroki Aoki, Masunori Matsuzaki
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 20 Issue 8 Pg. 1197-9 (Jun 2006) ISSN: 1530-6860 [Electronic] United States
• PMID: 16627625 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Proteins
• protein phosphatase inhibitor-2
• Phosphoprotein Phosphatases
• Protein Phosphatase 1

Topics

• Animals
• Cardiac Output, Low (physiopathology, therapy)
• Cardiomyopathy, Dilated (genetics, therapy)
• Cricetinae
• Dependovirus (genetics)
• Disease Progression
• Genetic Vectors
• Male
• Myocardium (enzymology)
• Myocytes, Cardiac (enzymology)
• Phosphoprotein Phosphatases (antagonists & inhibitors)
• Protein Phosphatase 1
• Proteins (genetics)
• Rats
• Rats, Wistar
• Survival Analysis
• Transduction, Genetic
• Ventricular Function, Left