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

Michio Yamada^*,, Yasuhiro Ikeda^*,,1, Masafumi Yano, Koichi Yoshimura^*, Shizuka Nishino^*, Hidekazu Aoyama^*,, Lili Wang, Hiroki Aoki^* and Masunori Matsuzaki^*,

^* Department of Molecular Cardiovascular Biology Yamaguchi University School of Medicine;

Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, Ube, Japan; and

Medical Genetics Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

¹Correspondence: Department of Molecular Cardiovascular Biology, Yamaguchi University School of Medicine, 1–1-1 Minami-Kogushi, Ube 755-8505, Japan. E-mail: ysikeda{at}yamaguchi-u.ac.jp

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 (PP1C) without inducing the corresponding increase in cytosolic PP1 activity. On the other hand, INH-2 delivery induced a decrease in microsomal PP1C, 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, M., Ikeda, Y., Yano, M., Yoshimura, K., Nishino, S., Aoyama, H., Wang, L., Aoki, H., and Matsuzaki, M. Inhibition of protein phosphatase 1 by inhibitor-2 gene delivery ameliorates heart failure progression in genetic cardiomyopathy.

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