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PP1 is a major serine/threonine phosphatase in mouse heart and has been shown to be involved in heart failure progression. The three PP1 catalytic subunits (α, β, and γ) have ~90% homology in the catalytic domains and unique N and C terminal sequences. The function of each isoform in the heart remains poorly understood. In this study, we created heart–specific PP1 deletion mice and assessed the cardiac performance.
Each PP1 isoform was conditionally deleted in the mouse heart using a Cre–loxP approach. LoxP sites were introduced into intron 1 and 3 of each PP1 isoform. LoxP–targeted lines were bred with mice expressing NKX2.5 promoter driven Cre to achieve isoform specific gene deletion in the heart. Echocardiography was performed in these mice at different ages. We also investigated protein phosphorylation status of selected PP1 targets that underlie cardiac contraction.
We found that heart–specific deletion of either PP1α or PPty caused a reduction of fractional shortening and worsening of cardiac function. However, PP1β deletion improved fractional shorting, indicating that each PP1 isoform plays different role in the heart. Interestingly, combined deletion of both PP1α and PP1β rescued the cardiac performance defects observed in PP1α deleted mice. Nuclear fractionation and immunocytochemistry data showed that PP1α or PP1γ were mainly localized in cytosol compared with the nuclear localization of PP1β. Furthermore, overexpression of PP1α or PP1γ decreased phosphorylation of phospholamban and myosin binding protein C, but not by that of PP1 β.
Our findings suggest that PP1 isoforms play distinct roles in the heart in regulating contractility.
Special Session North, Room 120
Sunday, March 10, 2013, 8:45 a.m.–9:00 a.m.
Session Title: Young Investigator Awards Competition: ACCF/Herman K. Gold Young Investigators Award in Molecular and Cellular Cardiology
Abstract Category: Molecular and Cellular Cardiology
Presentation Number: 402–7
- 2013 American College of Cardiology Foundation