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We investigated the effect of inhibition of protein phosphatase 1 (PP1) in heart failure. We used in vivohigh efficiency cardiac gene delivery system to express a human inhibitor-2 (I-2), an endogenous specific inhibitor of PP1, in UM-X7.1 cardiomyopathic hamster. Before cardiac gene delivery, we characterized time course of PP1 and protein kinase A (PKA) activity in progression of cardiomyopathy of UM-X7.1 hamster. Not only PP1 activity but also PKA activity was significantly elevated at 10 to 28weeks old of age in UM-7.1 hamster compared with normal hamster. We delivered recombinant adenovirus encoding I-2 or lacZ to UM-X7.1 hamster at 14 weeks old (I-2 and lacZ, n=9 in each group). Seven days after gene delivery, we assessed echocardiography, hemodynamics, biochemical and histological data of hearts. In echocardiography, left ventricular (LV) dimension significantly decreased with subtle increase % fractional shortening of the LV in I-2 treated hamsters, whereas lacZ treated hearts showed further progression of cardiomyopathy. Induction of brain natriuretic peptide was alleviated and PKA activity was significantly reduced in I-2 treated hearts, suggesting mitigated β-adrenergic signaling. In conclusion, these data indicate that inhibition of PP1 is beneficial for preventing progressive LV dysfunction by modifying excessive β-adrenergic stimulation and can be a potential target for treatment of genetic cardiomyopathy and associated heart failure.