Abstract 205: Differing Cardiac Phenotypes Between PP1α and PP1β Heart-Specific Gene-Deleted Mice
Background: Protein phosphatase 1 is the major protein serine/threonine phosphatase in nearly all mammalian tissues, where it consists of three isoforms PP1α, PP1β, and PP1γ. However, the redundant or specific roles of each isoform in the heart is not known
Methods: 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 PP1α and PP1β. Both loxP-targeted lines were bred with mice expressing β-myosin heavy chain 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 and calcium handling from the hearts of these deleted mice.
Results: Heart-specific deletion of PP1α caused a reduction of fractional shortening and worsening of cardiac function. Two weeks after transaortic constriction (TAC), PP1α deleted mice had greater increases in heart-weight to body-weight ratio compared with control mice, suggesting that PP1α was important for proper cardiac compensation. Interestingly, however, combined deletion of both PP1α and PP1β rescued the cardiac performance defects observed in PP1α deleted mice. Mechanistically, we found that deletion of PP1αβ led to increased phospholamban serine 16 and threonine 17 phosphorylation compared to that of PP1α. In conclusion, we showed that PP1 isoforms play distinct roles in the heart in regulating contractility and compensation after pressure overload stimulation.
- © 2012 by American Heart Association, Inc.