Protein Phosphatase-1 and Inhibitor-1

Abnormal calcium cycling, characteristic of experimental and human heart failure, is associated with impaired sarcoplasmic reticulum calcium uptake activity, as described above. This reflects decreases in cAMP-pathway signaling and increases in type 1 phosphatase activity, which results in decreased contractile force in the heart (Figure 1). The increased protein phosphatase 1 activity is partially due to dephosphorylation and inactivation of its Inhibitor-1, promoting dephosphorylation of phospholamban and inhibition of the sarcoplasmic reticulum calcium-pump.

Figure 1: The Balance of Protein Kinases and Phosphatases

Cardiac-specific expression of a constitutively active Inhibitor-1 results in selective enhancement of phospholamban phosphorylation and augmented cardiac contractility at the cellular and intact animal levels through inhibition of Protein Phosphatase-1. Furthermore, the ß-adrenergic response is enhanced in the transgenic hearts compared with wild types. On aortic constriction, the hypercontractile cardiac function is maintained, hypertrophy is attenuated and there is no decompensation in the transgenics compared with wild-type controls.

Figure 2: I-1 Protects Against Hypertrophy Induced by Aortic Banding

These studies in cardiac protection were extended to test the hypothesis that acute I-1 overexpression in the heart could restore cardiac function in failing hearts. As the Pressure-Volume curves below demonstrate, adenoviral gene delivery of the active inhibitor-1 greatly restores function and partially reverses remodeling in the setting of pre-existing heart failure. These studies are done in collaboration with Dr. Roger Hajjar's lab at Harvard Medical School.

Figure 3: Pressure-Volume Curves Demonstrating I-1 Rescue of Failing Hearts.

Thus, the inhibitor 1 of the type 1 phosphatase may represent an attractive new therapeutic target. Future studies will include analysis of the effect of PKC phosphorylation of Inhibitor-1 and the role of Inhibitor-1 in preconditioning and ischemia.