Inhibition of protein phosphatase 1 by inhibitor-2 gene delivery ameliorates heart failure progression in genetic cardiomyopathy.
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.
Yamada
Michio
M
Department of Molecular Cardiovascular Biology, Yamaguchi University School of Medicine, 1-1-1 Minami-Kogushi, Ube 755-8505, Japan.
Ikeda
Yasuhiro
Y
Yano
Masafumi
M
Yoshimura
Koichi
K
Nishino
Shizuka
S
Aoyama
Hidekazu
H
Wang
Lili
L
Aoki
Hiroki
H
Matsuzaki
Masunori
M
D000818:Animals; D002303:Cardiac Output, Low / Q000503:physiopathology / Q000628:therapy*; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000628:therapy*; D006224:Cricetinae; D000229:Dependovirus / Q000235:genetics; D018450:Disease Progression; D005822:Genetic Vectors; D008297:Male; D009206:Myocardium / Q000201:enzymology*; D032383:Myocytes, Cardiac / Q000201:enzymology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D054645:Protein Phosphatase 1; D011506:Proteins / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D016019:Survival Analysis; D014161:Transduction, Genetic; D016277:Ventricular Function, Left; D000097847:Protein Phosphatase Inhibitory Proteins
D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D011506:Proteins; C024833:protein phosphatase inhibitor-2; D000097847:Protein Phosphatase Inhibitory Proteins